The multidimensional biology of SKP2: mechanisms, pathologies, and emerging therapeutic frontiers

Abstract

S phase kinase-associated protein 2 (SKP2), the rate-limiting substrate receptor of the SKP1-Cullin1-F-box (SCF) E3 ubiquitin ligase complex, is considered a canonical gatekeeper of cell cycle progression. However, accumulating evidence indicates that SKP2 functions as a multifaceted signaling hub that orchestrates metabolic reprogramming, the DNA damage response, stem cell maintenance, and synaptic plasticity. Dysregulation of these processes contributes to the pathogenesis of many types of human diseases, including cancer. This review provides a comprehensive overview of the diverse biological roles of SKP2, beginning with detailed insights into the assembly and substrate-recognition mechanisms of the Cullin1-SKP2-CKS1 protein complex. Moreover, we explore the functional dichotomy of SKP2, expanding its classic role in K48-linked proteasomal degradation to include noncanonical roles in K63-linked signaling activation. Furthermore, we elucidate the pathogenic implications of SKP2 in malignancies such as castration-resistant prostate cancer (CRPC) and triple-negative breast cancer (TNBC), as well as neurodegenerative conditions, including Alzheimer’s disease. More importantly, we evaluate therapeutic approaches targeting SKP2, highlighting the shift from first-generation protein-protein interaction (PPI) inhibitors to next-generation degraders, including the novel induced-proximity degrader SKPer1 and emerging PROTACs. Finally, to bridge the gap to clinical translation, we discuss the remaining druggability challenges and future directions for pharmacological optimization.

Keywords

SKP2 / E3 Ubiquitin Ligase / Metabolic Reprogramming / Tumorigenesis / Oncogene / Cell Cycle / PROTACs

References

[1] Popovic D, Vucic D, Dikic I: Ubiquitination in Disease Pathogenesis and Treatment. Nature Medicine 2014, 20: 1242-1253.

[2] Nakayama KI, Nakayama K: Ubiquitin Ligases: Cell-Cycle Control and Cancer. Nature Reviews Cancer 2006, 6: 369-381.

[3] Hershko A, Ciechanover A: The Ubiquitin System. Annual Review of Biochemistry 1998, 67: 425-479.

[4] Petroski MD, Deshaies RJ: Function and Regulation of Cullin-RING Ubiquitin Ligases. Nature Reviews Molecular Cell Biology 2005, 6: 9-20.

[5] Carrano AC, Eytan E, Hershko A, Pagano M: SKP2 is Required for Ubiquitin-Mediated Degradation of the CDK Inhibitor p27. Nature Cell Biology 1999, 1: 193-199.

[6] Tsvetkov LM, Yeh KH, Lee SJ, Sun H, Zhang H: p27^Kip1 Ubiquitination and Degradation is Regulated by the SCF^Skp2 Complex through Phosphorylated Thr187 in p27 . Current Biology 1999, 9: 661-664.

[7] Chan CH, Li CF, Yang WL, Gao Y, Lee SW, Feng Z, et al.: The Skp2-SCF E3 Ligase Regulates Akt Ubiquitination, Glycolysis, Herceptin Sensitivity, and Tumorigenesis. Cell 2012, 149: 1098-1111.

[8] Liu J, Peng Y, Shi L, Wan L, Inuzuka H, Long J, et al.: Skp2 Dictates Cell Cycle-Dependent Metabolic Oscillation between Glycolysis and TCA Cycle. Cell Research 2021, 31: 80-93.

[9] Jia J, Yan D, Wang Y, Liu M, Jia Z, Luo L, et al.: Skp2 Regulates DNA Damage Repair and Apoptosis via Interaction with Ku70. Experimental Cell Research 2020, 397: 112335.

[10] Wang J, Han F, Wu J, Lee SW, Chan CH, Wu CY, et al.: The Role of Skp2 in Hematopoietic Stem Cell Quiescence, Pool Size, and Self-Renewal. Blood 2011, 118: 5429-5438.

[11] Wang J, Han F, Lee SW, Wu J, Chan CH, Zhang X, et al.: E3-Ligase Skp2 Regulates β-Catenin Expression and Maintains Hematopoietic Stem Cell Homing. Biochemical and Biophysical Research Communications 2014, 445: 566-571.

[12] Gassen NC, Niemeyer D, Muth D, Corman VM, Martinelli S, Gassen A, et al.: SKP2 Attenuates Autophagy through Beclin1-Ubiquitination and its Inhibition Reduces MERS-Coronavirus Infection. Nature Communications 2019, 10: 5770.

[13] Chan CH, Morrow JK, Li CF, Gao Y, Jin G, Moten A, et al.: Pharmacological Inactivation of Skp2 SCF Ubiquitin Ligase Restricts Cancer Stem Cell Traits and Cancer Progression. Cell 2013, 154: 556-568.

[14] Jin G, Lee SW, Zhang X, Cai Z, Gao Y, Chou PC, et al.: Skp2-Mediated RagA Ubiquitination Elicits a Negative Feedback to Prevent Amino-Acid-Dependent mTORC1 Hyperactivation by Recruiting GATOR1. Molecular Cell 2015, 58: 989-1000.

[15] Shin HJ, Kim H, Oh S, Lee JG, Kee M, Ko HJ, et al.: AMPK-SKP2-CARM1 Signalling Cascade in Transcriptional Regulation of Autophagy. Nature 2016, 534: 553-557.

[16] Shin HR, Kim H, Kim KI, Baek SH: Epigenetic and Transcriptional Regulation of Autophagy. Autophagy 2016, 12: 2248-2249.

[17] Lu W, Liu S, Li B, Xie Y, Adhiambo C, Yang Q, et al.: SKP2 Inactivation Suppresses Prostate Tumorigenesis by Mediating JARID1B Ubiquitination. Oncotarget 2015, 6: 771-788.

[18] Frescas D, Pagano M: Deregulated Proteolysis by the F-box Proteins SKP2 and β-TrCP: Tipping the Scales of Cancer. Nature Reviews Cancer 2008, 8: 438-449.

[19] Ruan D, He J, Li CF, Lee HJ, Liu J, Lin HK, et al.: Skp2 Deficiency Restricts the Progression and Stem Cell Features of Castration-Resistant Prostate Cancer by Destabilizing Twist. Oncogene 2017, 36: 4299-4310.

[20] Clement E, Inuzuka H, Nihira NT, Wei W, Toker A: Skp2-Dependent Reactivation of AKT Drives Resistance to PI3K Inhibitors. Science Signaling 2018, 11: eaao3810.

[21] Wang W, Gu XH, Li M, Cheng ZJ, Tian S, Liao Y, et al.: MicroRNA-155-5p Targets SKP2, Activates IKKβ, Increases Aβ Aggregation, and Aggravates a Mouse Alzheimer Disease Model. Journal of Neuropathology and Experimental Neurology 2022, 81: 16-26.

[22] Jakhmola-Mani R, Islam A, Katare DP: Liver-Brain Axis in Sporadic Alzheimer’s Disease: Role of Ten Signature Genes in a Mouse Model. CNS & Neurological Disorders Drug Targets 2021, 20: 871-885.

[23] Kamel EM, Khadrawy SM, Allam AA, Ahmed NA, Aba Alkhayl FF, Lamsabhi AM: Targeting the Skp2-Cks1 Protein-Protein Interaction: Structures, Assays, and Preclinical Inhibitors. European Journal of Pharmacology 2025, 1006: 178129.

[24] Sun X, Gao H, Yang Y, He M, Wu Y, Song Y, et al.: PROTACs: Great Opportunities for Academia and Industry. Signal Transduction and Targeted Therapy 2019, 4: 64.

[25] Chu Y, Chen S, Yang M, Chen Y, Fang H, Huang P, et al.: A Rapid Imaging-Based Screen for Induced-Proximity Degraders Identifies a Potent Degrader of Oncoprotein SKP2. Nature Biotechnology 2025. doi: 10.1038/s41587-025-02793-8

[26] Ciechanover A: Proteolysis: From the Lysosome to Ubiquitin and the Proteasome. Nature Reviews Molecular Cell Biology 2005, 6: 79-87.

[27] Dikic I, Elazar Z: Mechanism and Medical Implications of Mammalian Autophagy. Nature Reviews Molecular Cell Biology 2018, 19: 349-364.

[28] Zheng N, Shabek N: Ubiquitin Ligases: Structure, Function, and Regulation. Annual Review Biochemistry 2017, 86: 129-157.

[29] Pohl C, Dikic I: Cellular Quality Control by the Ubiquitin-Proteasome System and Autophagy. Science 2019, 366: 818-822.

[30] Hershko A, Ciechanover A, Heller H, Haas AL, Rose IA: Proposed Role of ATP in Protein Breakdown: Conjugation of Protein with Multiple Chains of the Polypeptide of ATP-Dependent Proteolysis. Proceedings of the National Academy of Sciences of the United States of America 1980, 77: 1783-1786.

[31] Ciechanover A: The Unravelling of the Ubiquitin System. Nature Reviews Molecular Cell Biology 2015, 16: 322-324.

[32] Liu H, Bui Q, Hassenstab J, Gordon BA, Benzinger TLS, Timsina J, et al.: Ubiquitin-Proteasome System in the Different Stages of Dominantly Inherited Alzheimer’s Disease. Alzheimer’s & Dementia: The Journal of the Alzheimer’s Association 2025, 21: e70243.

[33] Bard JAM, Goodall EA, Greene ER, Jonsson E, Dong KC, Martin A: Structure and Function of the 26S Proteasome. Annual Review Biochemistry 2018, 87: 697-724.

[34] Schulman BA, Harper JW: Ubiquitin-Like Protein Activation by E1 Enzymes: The Apex for Downstream Signalling Pathways. Nature Reviews Molecular Cell Biology 2009, 10: 319-331.

[35] Smalle J, Vierstra RD: The Ubiquitin 26S Proteasome Proteolytic Pathway. Annual Review of Plant Biology 2004, 55: 555-590.

[36] Verma R, Aravind L, Oania R, McDonald WH, Yates JR 3rd, Koonin EV, et al.: Role of Rpn11 Metalloprotease in Deubiquitination and Degradation by the 26S Proteasome. Science 2002, 298: 611-615.

[37] Chen S, Wu J, Lu Y, Ma YB, Lee BH, Yu Z, et al.: Structural Basis for Dynamic Regulation of the Human 26S Proteasome. Proceedings of the National Academy of Sciences of the United States of America 2016, 113: 12991-12996.

[38] Harper JW, Schulman BA: Cullin-RING Ubiquitin Ligase Regulatory Circuits: A Quarter Century Beyond the F-Box Hypothesis. Annual Review Biochemistry 2021, 90: 403-429.

[39] Hua Z, Vierstra RD: The Cullin-RING Ubiquitin-Protein Ligases. Annual Review of Plant Biology 2011, 62: 299-334.

[40] Qi Y, Rezaeian AH, Wang J, Huang D, Chen H, Inuzuka H, et al.: Molecular Insights and Clinical Implications for the Tumor Suppressor Role of SCF^FBXW7 E3 Ubiquitin Ligase . Biochimica et Biophysica Acta (BBA) - Reviews on Cancer 2024, 1879: 189140.

[41] Zhou W, Wei W, Sun Y: Genetically Engineered Mouse Models for Functional Studies of SKP1-CUL1-F-Box-Protein (SCF) E3 Ubiquitin Ligases. Cell Research 2013, 23: 599-619.

[42] Asmamaw MD, Liu Y, Zheng YC, Shi XJ, Liu HM: Skp2 in the Ubiquitin-Proteasome System: A Comprehensive Review. Medicinal Research Reviews 2020, 40: 1920-1949.

[43] Rotin D, Kumar S: Physiological Functions of the HECT Family of Ubiquitin Ligases. Nature Reviews Molecular Cell Biology 2009, 10: 398-409.

[44] Song MS, Pandolfi PP: The HECT Family of E3 Ubiquitin Ligases and PTEN. Seminars in Cancer Biology 2022, 85: 43-51.

[45] Goto J, Otaki Y, Watanabe T, Watanabe M: The Role of HECT-Type E3 Ligase in the Development of Cardiac Disease. International Journal of Molecular Sciences 2021, 22: 6065.

[46] Walden H, Rittinger K: RBR Ligase-Mediated Ubiquitin Transfer: A Tale with many Twists and Turns. Nature Structural & Molecular Biology 2018, 25: 440-445.

[47] Wenzel DM, Lissounov A, Brzovic PS, Klevit RE: UBCH7 Reactivity Profile Reveals Parkin and HHARI to be RING/HECT Hybrids. Nature 2011, 474: 105-108.

[48] Wauer T, Komander D: Structure of the Human Parkin Ligase Domain in an Autoinhibited State. EMBO Journal 2013, 32: 2099-2112.

[49] Pickrell AM, Youle RJ: The Roles of PINK1, Parkin, and Mitochondrial Fidelity in Parkinson’s Disease. Neuron 2015, 85: 257-273.

[50] Komander D, Rape M: The Ubiquitin Code. Annual Review Biochemistry 2012, 81: 203-229.

[51] Dikic I, Schulman BA: An Expanded Lexicon for the Ubiquitin Code. Nature Reviews Molecular Cell Biology 2023, 24: 273-287.

[52] Kolla S, Ye M, Mark KG, Rapé M: Assembly and Function of Branched Ubiquitin Chains. Trends in Biochemical Sciences 2022, 47: 759-771.

[53] Tracz M, Bialek W: Beyond K48 and K63: Non-Canonical Protein Ubiquitination. Cellular & Molecular Biology Letters 2021, 26: 1.

[54] Lim KL, Lim GG: K63-Linked Ubiquitination and Neurodegeneration. Neurobiology of Disease 2011, 43: 9-16.

[55] Wickliffe KE, Williamson A, Meyer HJ, Kelly A, Rape M: K11-Linked Ubiquitin Chains as Novel Regulators of Cell Division. Trends in Cell Biology 2011, 21: 656-663.

[56] Emmerich CH, Schmukle AC, Walczak H: The Emerging Role of Linear Ubiquitination in Cell Signaling. Science Signaling 2011, 4: re5.

[57] van Huizen M, Kikkert M: The Role of Atypical Ubiquitin Chains in the Regulation of the Antiviral Innate Immune Response. Frontiers in Cell and Developmental Biology 2019, 7: 392.

[58] Lee YR, Chen M, Lee JD, Zhang J, Lin SY, Fu TM, et al.: Reactivation of PTEN Tumor Suppressor for Cancer Treatment through Inhibition of a MYC-WWP1 Inhibitory Pathway. Science 2019, 364: eaau0159.

[59] Yau R, Rape M: The Increasing Complexity of the Ubiquitin Code. Nature Cell Biology 2016, 18: 579-586.

[60] Draczkowski P, Chen SN, Chen T, Wang YS, Shih HA, Huang JYC, et al.: Structural Basis of K11/K48-Branched Ubiquitin Chain Recognition by the Human 26S Proteasome. Nature Communications 2025, 16: 9094.

[61] Yau RG, Doerner K, Castellanos ER, Haakonsen DL, Werner A, Wang N, et al.: Assembly and Function of Heterotypic Ubiquitin Chains in Cell-Cycle and Protein Quality Control. Cell 2017, 171: 918-933.e20.

[62] Ohtake F, Saeki Y, Ishido S, Kanno J, Tanaka K: The K48-K63 Branched Ubiquitin Chain Regulates NF-κB Signaling. Molecular Cell 2016, 64: 251-266.

[63] Ohtake F, Tsuchiya H, Saeki Y, Tanaka K: K63 Ubiquitylation Triggers Proteasomal Degradation by Seeding Branched Ubiquitin Chains. Proceedings of the National Academy of Sciences of the United States of America 2018, 115: E1401-E1408.

[64] Nijman SM, Luna-Vargas MP, Velds A, Brummelkamp TR, Dirac AM, Sixma TK, et al.: A Genomic and Functional Inventory of Deubiquitinating Enzymes. Cell 2005, 123: 773-786.

[65] Liao Y, Liu N, Xia X, Guo Z, Li Y, Jiang L, et al.: USP10 Modulates the SKP2/Bcr-Abl Axis via Stabilizing SKP2 in Chronic Myeloid Leukemia. Cell Discovery 2019, 5: 24.

[66] Cai Z, Moten A, Peng D, Hsu CC, Pan BS, Manne R, et al.: The Skp2 Pathway: A Critical Target for Cancer Therapy. Seminars in Cancer Biology 2020, 67(Pt 2): 16-33.

[67] Sato Y: Advances in Enzymatic Reconstitution of Ubiquitin Chains and Substrate Ubiquitination. The Journal of Biochemistry 2026, 179: 155-162.

[68] Finley D, Ulrich HD, Sommer T, Kaiser P: The Ubiquitin-Proteasome System of Saccharomyces Cerevisiae . Genetics 2012, 192: 319-360.

[69] Stewart MD, Ritterhoff T, Klevit RE, Brzovic PS: E2 Enzymes: More than just Middle Men. Cell Research 2016, 26: 423-440.

[70] Sarikas A, Hartmann T, Pan ZQ: The Cullin Protein Family. Genome Biology 2011, 12: 220.

[71] Zheng N, Schulman BA, Song L, Miller JJ, Jeffrey PD, Wang P, et al.: Structure of the Cul1-Rbx1-Skp1-F Box^Skp2 SCF Ubiquitin Ligase Complex . Nature 2002, 416: 703-709.

[72] Wang Z, Liu P, Inuzuka H, Wei W: Roles of F-box Proteins in Cancer. Nature Reviews Cancer 2014, 14: 233-247.

[73] Tekcham DS, Chen D, Liu Y, Ling T, Zhang Y, Chen H, et al.: F-box Proteins and Cancer: An Update from Functional and Regulatory Mechanism to Therapeutic Clinical Prospects. Theranostics 2020, 10: 4150-4167.

[74] Ho MS, Tsai PI, Chien CT: F-box Proteins: The Key to Protein Degradation. Journal of Biomedical Science 2006, 13: 181-191.

[75] Randle SJ, Laman H: F-box Protein Interactions with the Hallmark Pathways in Cancer. Seminars in Cancer Biology 2016, 36: 3-17.

[76] Wu G, Xu G, Schulman BA, Jeffrey PD, Harper JW, Pavletich NP: Structure of a β-TrCP1-Skp1-β-Catenin Complex: Destruction Motif Binding and Lysine Specificity of the SCF^β-TrCP1 Ubiquitin Ligase . Molecular Cell 2003, 11: 1445-1456.

[77] Davis RJ, Welcker M, Clurman BE: Tumor Suppression by the Fbw7 Ubiquitin Ligase: Mechanisms and Opportunities. Cancer Cell 2014, 26: 455-464.

[78] Yumimoto K, Nakayama KI: Recent Insight into the Role of FBXW7 as a Tumor Suppressor. Seminars in Cancer Biology 2020, 67: 1-15.

[79] Kamura T, Koepp DM, Conrad MN, Skowyra D, Moreland RJ, Iliopoulos O, et al.: Rbx1, a Component of the VHL Tumor Suppressor Complex and SCF Ubiquitin Ligase. Science (New York, N.Y.) 1999, 284: 657-661.

[80] Hon WC, Wilson MI, Harlos K, Claridge TD, Schofield CJ, Pugh CW, et al.: Structural Basis for the Recognition of Hydroxyproline in HIF-1 Alpha by pVHL. Nature 2002, 417: 975-978.

[81] Maxwell PH, Wiesener MS, Chang GW, Clifford SC, Vaux EC, Cockman ME, et al.: The Tumour Suppressor Protein VHL Targets Hypoxia-Inducible Factors for Oxygen-Dependent Proteolysis. Nature 1999, 399: 271-275.

[82] Liao C, Hu L, Zhang Q: Von Hippel-Lindau Protein Signalling in Clear Cell Renal Cell Carcinoma. Nature Reviews Urology 2024, 21: 662-675.

[83] Genschik P, Sumara I, Lechner E: The Emerging Family of CULLIN3-RING Ubiquitin Ligases (CRL3s): Cellular Functions and Disease Implications. The EMBO Journal 2013, 32: 2307-2320.

[84] Pintard L, Willis JH, Willems A, Johnson JL, Srayko M, Kurz T, et al.: The BTB Protein MEL-26 is a Substrate-Specific Adaptor of the CUL-3 Ubiquitin-Ligase. Nature 2003, 425: 311-316.

[85] Stogios PJ, Privé GG: The BACK Domain in BTB-kelch Proteins. Trends in Biochemical Sciences 2004, 29: 634-637.

[86] Yamamoto M, Kensler TW, Motohashi H: The KEAP1-NRF2 System: A Thiol-Based Sensor-Effector Apparatus for Maintaining Redox Homeostasis. Physiological Reviews 2018, 98: 1169-1203.

[87] Canning P, Sorrell FJ, Bullock AN: Structural Basis of Keap1 Interactions with Nrf2. Free Radical Biology & Medicine 2015, 88: 101-107.

[88] An J, Wang C, Deng Y, Yu L, Huang H: Destruction of Full-Length Androgen Receptor by Wild-Type SPOP, but not Prostate-Cancer-Associated Mutants. Cell Reports 2014, 6: 657-669.

[89] Gan W, Dai X, Lunardi A, Li Z, Inuzuka H, Liu P, et al.: SPOP Promotes Ubiquitination and Degradation of the ERG Oncoprotein to Suppress Prostate Cancer Progression. Molecular Cell 2015, 59: 917-930.

[90] Dai X, Gan W, Li X, Wang S, Zhang W, Huang L, et al.: Prostate Cancer-Associated SPOP Mutations Confer Resistance to BET Inhibitors Through Stabilization of BRD4 . Nature Medicine 2017, 23: 1063-1071.

[91] Wang Z, Song Y, Ye M, Dai X, Zhu X, Wei W: The Diverse Roles of SPOP in Prostate Cancer and Kidney Cancer. Nature Reviews. Urology 2020, 17: 339-350.

[92] Biedermann S, Hellmann H: WD40 and CUL4-Based E3 Ligases: Lubricating all Aspects of Life. Trends in Plant Science 2011, 16: 38-46.

[93] Angers S, Li T, Yi X, MacCoss MJ, Moon RT, Zheng N: Molecular Architecture and Assembly of the DDB1-CUL4A Ubiquitin Ligase Machinery. Nature 2006, 443: 590-593.

[94] Petzold G, Fischer ES, Thomä NH: Structural Basis of Lenalidomide-Induced CK1α Degradation by the CRL4^CRBN Ubiquitin Ligase . Nature 2016, 532: 127-130.

[95] Lopez-Girona A, Mendy D, Ito T, Miller K, Gandhi AK, Kang J, et al.: Cereblon is a Direct Protein Target for Immunomodulatory and Antiproliferative Activities of Lenalidomide and Pomalidomide. Leukemia 2012, 26: 2326-2335.

[96] Ito T, Ando H, Suzuki T, Ogura T, Hotta K, Imamura Y, et al.: Identification of a Primary Target of Thalidomide Teratogenicity. Science (New York, N.Y.) 2010, 327: 1345-1350.

[97] Krönke J, Fink EC, Hollenbach PW, MacBeth KJ, Hurst SN, Udeshi ND, et al.: Lenalidomide Induces Ubiquitination and Degradation of CK1α in del(5q) MDS. Nature 2015, 523: 183-188.

[98] Fischer ES, Böhm K, Lydeard JR, Yang H, Stadler MB, Cavadini S, et al.: Structure of the DDB1-CRBN E3 Ubiquitin Ligase in Complex with Thalidomide. Nature 2014, 512: 49-53.

[99] Zhao Y, Xiong X, Sun Y: Cullin-RING Ligase 5: Functional Characterization and its Role in Human Cancers. Seminars in Cancer Biology 2020, 67: 61-79.

[100] Adachi Y, Terakura S, Osaki M, Okuno Y, Sato Y, Sagou K, et al.: Cullin-5 Deficiency Promotes Chimeric Antigen Receptor T Cell Effector Functions Potentially Via the Modulation of JAK/STAT Signaling Pathway. Nature Communications 2024, 15: 10376.

[101] Yu X, Yu Y, Liu B, Luo K, Kong W, Mao P, et al.: Induction of APOBEC3G Ubiquitination and Degradation by an HIV-1 Vif-Cul5-SCF Complex. Science (New York, N.Y.) 2003, 302: 1056-1060.

[102] Lumpkin RJ, Baker RW, Leschziner AE, Komives EA: Structure and Dynamics of the ASB9 CUL-RING E3 Ligase. Nature Communications 2020, 11: 2866.

[103] Stanley BJ, Ehrlich ES, Short L, Yu Y, Xiao Z, Yu XF, et al.: Structural Insight into the Human Immunodeficiency Virus Vif SOCS Box and its Role in Human E3 Ubiquitin Ligase Assembly. Journal of Virology 2008, 82: 8656-8663.

[104] Shi L, Du D, Peng Y, Liu J, Long J: The Functional Analysis of Cullin 7 E3 Ubiquitin Ligases in Cancer. Oncogenesis 2020, 9: 98.

[105] Hopf LVM, Baek K, Klügel M, von Gronau S, Xiong Y, Schulman BA: Structure of CRL7^FBXW8 Reveals Coupling with CUL1-RBX1/ROC1 for Multi-Cullin-RING E3-Catalyzed Ubiquitin Ligation . Nature Structural & Molecular Biology 2022, 29: 854-862.

[106] Litterman N, Ikeuchi Y, Gallardo G, O’Connell BC, Sowa ME, Gygi SP, et al.: An OBSL1-Cul7^Fbxw8 Ubiquitin Ligase Signaling Mechanism Regulates Golgi Morphology and Dendrite Patterning . PLoS Biology 2011, 9: e1001060.

[107] Huber C, Dias-Santagata D, Glaser A, O’Sullivan J, Brauner R, Wu K, et al.: Identification of Mutations in CUL7 in 3-M Syndrome . Nature Genetics 2005, 37: 1119-1124.

[108] Nikolaev AY, Li M, Puskas N, Qin J, Gu W: Parc: A Cytoplasmic Anchor for p53. Cell 2003, 112: 29-40.

[109] Ortolano NA, Romero-Morales AI, Rasmussen ML, Bodnya C, Kline LA, Joshi P, et al.: A Proteomics Approach for the Identification of Cullin-9 (CUL9) Related Signaling Pathways in Induced Pluripotent Stem Cell Models. PloS One 2021, 16: e0248000.

[110] Pei XH, Bai F, Li Z, Smith MD, Whitewolf G, Jin R, et al.: Cytoplasmic CUL9/PARC Ubiquitin Ligase is a Tumor Suppressor and Promotes p53-Dependent Apoptosis . Cancer Research 2011, 71: 2969-2977.

[111] Horn-Ghetko D, Hopf LVM, Tripathi-Giesgen I, Du J, Kostrhon S, Vu DT, et al.: Noncanonical Assembly, Neddylation and Chimeric Cullin-RING/RBR Ubiquitylation by the 1.8 MDa CUL9 E3 Ligase Complex. Nature Structural & Molecular Biology 2024, 31: 1083-1094.

[112] Mason B, Laman H: The FBXL Family of F-box Proteins: Variations on a Theme. Open Biology 2020, 10: 200319.

[113] Hotton SK, Callis J: Regulation of Cullin RING Ligases. Annual Review of Plant Biology 2008, 59: 467-489.

[114] Pan ZQ, Kentsis A, Dias DC, Yamoah K, Wu K: Nedd8 on Cullin: Building an Expressway to Protein Destruction. Oncogene 2004, 23: 1985-1997.

[115] Duda DM, Borg LA, Scott DC, Hunt HW, Hammel M, Schulman BA: Structural Insights into NEDD8 Activation of Cullin-RING Ligases: Conformational Control of Conjugation. Cell 2008, 134: 995-1006.

[116] Goldenberg SJ, Cascio TC, Shumway SD, Garbutt KC, Liu J, Xiong Y, et al.: Structure of the Cand1-Cul1-Roc1 Complex Reveals Regulatory Mechanisms for the Assembly of the Multisubunit Cullin-Dependent Ubiquitin Ligases. Cell 2004, 119: 517-528.

[117] Pierce NW, Lee JE, Liu X, Sweredoski MJ, Graham RL, Larimore EA, et al.: Cand1 Promotes Assembly of New SCF Complexes Through Dynamic Exchange of F Box Proteins. Cell 2013, 153: 206-215.

[118] Hao B, Zheng N, Schulman BA, Wu G, Miller JJ, Pagano M, et al.: Structural Basis of the Cks1-Dependent Recognition of p27(Kip1) by the SCF(Skp2) Ubiquitin Ligase. Molecular Cell 2005, 20: 9-19.

[119] Morgan DO: Regulation of the APC and the Exit from Mitosis. Nature Cell Biology 1999, 1: E47-E53.

[120] Rowland RJ, Heath R, Maskell D, Thompson RF, Ranson NA, Blaza JN, et al.: Cryo-EM Structure of SKP1-SKP2-CKS1 in Complex with CDK2-Cyclin A-p27KIP1. Scientific Reports 2023, 13: 10718.

[121] Wang W, Ungermannova D, Chen L, Liu X: Molecular and Biochemical Characterization of the Skp2-Cks1 Binding Interface. The Journal of Biological Chemistry 2004, 279: 51362-51369.

[122] Yao ZP, Zhou M, Kelly SE, Seeliger MA, Robinson CV, Itzhaki LS: Activation of Ubiquitin Ligase SCF^Skp2 by Cks1: Insights from Hydrogen Exchange Mass Spectrometry . Journal of Molecular Biology 2006, 363: 673-686.

[123] Bulatov E, Ciulli A: Targeting Cullin-RING E3 Ubiquitin Ligases for Drug Discovery: Structure, Assembly and Small-Molecule Modulation. The Biochemical Journal 2015, 467: 365-386.

[124] Bretones G, Acosta JC, Caraballo JM, Ferrándiz N, Gómez-Casares MT, Albajar M, et al.: SKP2 Oncogene is a Direct MYC Target Gene and MYC Down-Regulates p27(KIP1) Through SKP2 in Human Leukemia Cells. The Journal of Biological Chemistry 2011, 286: 9815-9825.

[125] Chen L, Tweddle DA: p53, SKP2, and DKK3 as MYCN Target Genes and Their Potential Therapeutic Significance . Frontiers in Oncology 2012, 2: 173.

[126] Schneider G, Saur D, Siveke JT, Fritsch R, Greten FR, Schmid RM: IKKα Controls p52/RelB at the skp2 Gene Promoter to Regulate G1- to S-phase Progression. The EMBO Journal 2006, 25: 3801-3812.

[127] Rodriguez S, Abundis C, Boccalatte F, Mehrotra P, Chiang MY, Yui MA, et al.: Therapeutic Targeting of the E3 Ubiquitin Ligase SKP2 in T-ALL. Leukemia 2020, 34: 1241-1252.

[128] Sarmento LM, Huang H, Limon A, Gordon W, Fernandes J, Tavares MJ, et al.: Notch1 Modulates Timing of G1-S Progression by Inducing SKP2 Transcription and p27 Kip1 Degradation. The Journal of Experimental Medicine 2005, 202: 157-168.

[129] Wu J, Lee SW, Zhang X, Han F, Kwan SY, Yuan X, et al.: Foxo3a Transcription Factor is a Negative Regulator of Skp2 and Skp2 SCF Complex. Oncogene 2013, 32: 78-85.

[130] Wang F, Chan CH, Chen K, Guan X, Lin HK, Tong Q: Deacetylation of FOXO3 by SIRT1 or SIRT2 Leads to Skp2-Mediated FOXO3 Ubiquitination and Degradation. Oncogene 2012, 31: 1546-1557.

[131] Li P, Chen T, Kuang P, Liu F, Li Z, Liu F, et al.: Aurora-A/FOXO3A/SKP2 Axis Promotes Tumor Progression in Clear Cell Renal Cell Carcinoma and Dual-Targeting Aurora-A/SKP2 Shows Synthetic Lethality. Cell Death & Disease 2022, 13: 606.

[132] Lee SM, Kaye KM, Slack FJ: Cellular microRNA-127-3p Suppresses Oncogenic Herpesvirus-Induced Transformation and Tumorigenesis Via Down-Regulation of SKP2. Proceedings of the National Academy of Sciences of the United States of America 2021, 118: e2105428118.

[133] Qi F, He T, Jia L, Song N, Guo L, Ma X, et al.: The miR-30 Family Inhibits Pulmonary Vascular Hyperpermeability in the Premetastatic Phase by Direct Targeting of Skp2. Clinical Cancer Research 2015, 21: 3071-3080.

[134] He Z, Chen L, Wang Q, Yin C, Hu J, Hu X, et al.: MicroRNA-186 Targets SKP2 to Induce p27^Kip1-Mediated Pituitary Tumor Cell Cycle Deregulation and Modulate Cell Proliferation . The Korean Journal of Physiology & Pharmacology 2019, 23: 171-179.

[135] Gao D, Inuzuka H, Tseng A, Chin RY, Toker A, Wei W: Phosphorylation by Akt1 Promotes Cytoplasmic Localization of Skp2 and Impairs APCCdh1-Mediated Skp2 Destruction. Nature Cell Biology 2009, 11: 397-408.

[136] Lin HK, Wang G, Chen Z, Teruya-Feldstein J, Liu Y, Chan CH, et al.: Phosphorylation-Dependent Regulation of Cytosolic Localization and Oncogenic Function of Skp2 by Akt/PKB. Nature Cell Biology 2009, 11: 420-432.

[137] Rodier G, Coulombe P, Tanguay PL, Boutonnet C, Meloche S: Phosphorylation of Skp2 Regulated by CDK2 and Cdc14B Protects it from Degradation by APC^Cdh1 in G1 Phase . The EMBO Journal 2008, 27: 679-691.

[138] Geng Q, Liu J, Gong Z, Chen S, Chen S, Li X, et al.: Phosphorylation by mTORC1 Stablizes Skp2 and Regulates its Oncogenic Function in Gastric Cancer. Molecular Cancer 2017, 16: 83.

[139] Wei W, Ayad NG, Wan Y, Zhang GJ, Kirschner MW, Kaelin WG Jr: Degradation of the SCF Component Skp2 in Cell-Cycle Phase G1 by the Anaphase-Promoting Complex. Nature 2004, 428: 194-198.

[140] Bashir T, Dorrello NV, Amador V, Guardavaccaro D, Pagano M: Control of the SCF^Skp2-Cks1 Ubiquitin Ligase by the APC/C^Cdh1 Ubiquitin Ligase . Nature 2004, 428: 190-193.

[141] Kona SV, Kalivendi SV: The USP10/13 Inhibitor, Spautin-1, Attenuates the Progression of Glioblastoma by Independently Regulating RAF-ERK Mediated Glycolysis and SKP2. Biochimica et Biophysica Acta (BBA) - Molecular Basis of Disease 2024, 1870: 167291.

[142] Zhang F, Zhao Y, Sun Y: USP2 is an SKP2 Deubiquitylase that Stabilizes Both SKP2 and its Substrates. The Journal of Biological Chemistry 2021, 297: 101109.

[143] Cope GA, Deshaies RJ: Targeted Silencing of Jab1/Csn5 in Human Cells Downregulates SCF Activity Through Reduction of F-box Protein Levels. BMC Biochemistry 2006, 7: 1.

[144] Inuzuka H, Gao D, Finley LW, Yang W, Wan L, Fukushima H, et al.: Acetylation-Dependent Regulation of Skp2 Function. Cell 2012, 150: 179-193.

[145] Zhang L, Wang C: F-box Protein Skp2: A Novel Transcriptional Target of E2F. Oncogene 2006, 25: 2615-2627.

[146] Yung Y, Walker JL, Roberts JM, Assoian RK: A Skp2 Autoinduction Loop and Restriction Point Control. The Journal of Cell Biology 2007, 178: 741-747.

[147] Shao Y, Ren W, Dai H, Yang F, Li X, Zhang S, et al.: SKP2 Contributes to AKT Activation by Ubiquitination Degradation of PHLPP1, Impedes Autophagy, and Facilitates the Survival of Thyroid Carcinoma. Molecules and Cells 2023, 46: 360-373.

[148] Germain D: Skp2 and Skp2B Team up Against Rb and p53. Cell Division 2011, 6: 1.

[149] Radke S, Pirkmaier A, Germain D: Differential Expression of the F-box Proteins Skp2 and Skp2B in Breast Cancer. Oncogene 2005, 24: 3448-3458.

[150] Zhang W, Cao L, Sun Z, Xu J, Tang L, Chen W, et al.: Skp2 is Over-Expressed in Breast Cancer and Promotes Breast Cancer Cell Proliferation. Cell Cycle 2016, 15: 1344-1351.

[151] Umanskaya K, Radke S, Chander H, Monardo R, Xu X, Pan ZQ, et al.: Skp2B Stimulates Mammary Gland Development by Inhibiting REA, the Repressor of the Estrogen Receptor. Molecular and Cellular Biology 2007, 27: 7615-7622.

[152] Chander H, Halpern M, Resnick-Silverman L, Manfredi JJ, Germain D: Skp2B Attenuates p53 Function by Inhibiting Prohibitin. The EMBO Reports 2010, 11: 220-225.

[153] Ullah Z, Lee CY, Depamphilis ML: Cip/Kip Cyclin-Dependent Protein Kinase Inhibitors and the Road to Polyploidy. Cell Division 2009, 4: 10.

[154] Liu W, Wu G, Li W, Lobur D, Wan Y: Cdh1-Anaphase-Promoting Complex Targets Skp2 for Destruction in Transforming Growth Factor Beta-Induced GROWTH Inhibition. Molecular and Cellular Biology 2007, 27: 2967-2979.

[155] Russo AA, Jeffrey PD, Patten AK, Massagué J, Pavletich NP: Crystal Structure of the p27^Kip1 Cyclin-Dependent-Kinase Inhibitor Bound to the Cyclin A-Cdk2 Complex . Nature 1996, 382: 325-331.

[156] Montagnoli A, Fiore F, Eytan E, Carrano AC, Draetta GF, Hershko A, et al.: Ubiquitination of p27 is Regulated by Cdk-Dependent Phosphorylation and Trimeric Complex Formation. Genes Development 1999, 13: 1181-1189.

[157] Cappell SD, Chung M, Jaimovich A, Spencer SL, Meyer T: Irreversible APC Cdh1 Inactivation Underlies the Point of No Return for Cell-Cycle Entry . Cell 2016, 166: 167-180.

[158] Yuan X, Srividhya J, De Luca T, Lee JH, Pomerening JR: Uncovering the Role of APC-Cdh1 in Generating the Dynamics of S-phase Onset. Molecular Biology of the Cell 2014, 25: 441-456.

[159] Bornstein G, Bloom J, Sitry-Shevah D, Nakayama K, Pagano M, Hershko A: Role of the SCF^Skp2 Ubiquitin Ligase in the Degradation of p21^Cip1 in S Phase . The Journal of Biological Chemistry 2003, 278: 25752-25757.

[160] Yu ZK, Gervais JL, Zhang H: Human CUL-1 Associates with the SKP1/SKP2 Complex and Regulates p21^CIP1/WAF1 and Cyclin D Proteins . Proceedings of the National Academy of Sciences of the United States of America 1998, 95: 11324-11329.

[161] Kamura T, Hara T, Kotoshiba S, Yada M, Ishida N, Imaki H, et al.: Degradation of p57 Kip2 Mediated by SCF Skp2-Dependent Ubiquitylation . Proceedings of the National Academy of Sciences of the United States of America 2003, 100: 10231-10236.

[162] Marti A, Wirbelauer C, Scheffner M, Krek W: Interaction Between Ubiquitin-Protein Ligase SCF^SKP2 and E2F-1 Underlies the Regulation of E2F-1 Degradation . Nature Cell Biology 1999, 1: 14-19.

[163] Song MS, Song SJ, Kim SY, Oh HJ, Lim DS: The Tumour Suppressor RASSF1A Promotes MDM2 Self-Ubiquitination by Disrupting the MDM2-DAXX-HAUSP Complex. The Embo Journal 2008, 27: 1863-1874.

[164] Li X, Zhao Q, Liao R, Sun P, Wu X: The SCF^Skp2 Ubiquitin Ligase Complex Interacts with the Human Replication Licensing Factor Cdt1 and Regulates Cdt1 Degradation . The Journal of Biological Chemistry 2003, 278: 30854-30858.

[165] Nishitani H, Sugimoto N, Roukos V, Nakanishi Y, Saijo M, Obuse C, et al.: Two E3 Ubiquitin Ligases, SCF-Skp2 and DDB1-Cul4, Target Human Cdt1 for Proteolysis. The Embo Journal 2006, 25: 1126-1136.

[166] Ellis M, Chew YP, Fallis L, Freddersdorf S, Boshoff C, Weiss RA, et al.: Degradation of p27^Kip Cdk Inhibitor Triggered by Kaposi’s Sarcoma Virus Cyclin-Cdk6 Complex . The Embo Journal 1999, 18: 644-653.

[167] Greene W, Zhang W, He M, Witt C, Ye F, Gao SJ: The Ubiquitin/Proteasome System Mediates Entry and Endosomal Trafficking of Kaposi’s Sarcoma-Associated Herpesvirus in Endothelial Cells. PLoS Pathogens 2012, 8: e1002703.

[168] Kops GJ, Dansen TB, Polderman PE, Saarloos I, Wirtz KW, Coffer PJ, et al.: Forkhead Transcription Factor FOXO3a Protects Quiescent Cells from Oxidative Stress. Nature 2002, 419: 316-321.

[169] Coomans de Brachène A, Demoulin JB: FOXO Transcription Factors in Cancer Development and Therapy. Cellular and Molecular Life Sciences 2016, 73: 1159-1172.

[170] Nho RS, Hergert P: FoxO3a and Disease Progression. World Journal of Biological Chemistry 2014, 5: 346-354.

[171] Stahl M, Dijkers PF, Kops GJ, Lens SM, Coffer PJ, Burgering BM, et al.: The Forkhead Transcription Factor FoxO Regulates Transcription of p27 Kip1 and Bim in Response to IL-2 . The Journal of Immunology 2002, 168: 5024-5031.

[172] Jiramongkol Y, Lam EW: FOXO Transcription Factor Family in Cancer and Metastasis. Cancer and Metastasis Reviews 2020, 39: 681-709.

[173] Kodani N, Nakae J: Tissue-Specific Metabolic Regulation of FOXO-Binding Protein: FOXO Does Not Act Alone. Cells 2020, 9: 702.

[174] Huang H, Regan KM, Wang F, Wang D, Smith DI, van Deursen JM, et al.: Skp2 Inhibits FOXO1 in Tumor Suppression Through Ubiquitin-Mediated Degradation. Proceedings of the National Academy of Sciences of the United States of America 2005, 102: 1649-1654.

[175] Huang H, Tindall DJ: Regulation of FOXO Protein Stability via Ubiquitination and Proteasome Degradation. Biochimica et Biophysica Acta (BBA) - Molecular Cell Research 2011, 1813: 1961-1964.

[176] Tedesco D, Lukas J, Reed SI: The pRb-Related Protein p130 is Regulated by Phosphorylation-Dependent Proteolysis via the Protein-Ubiquitin Ligase SCF^Skp2 . Genes Development 2002, 16: 2946-2957.

[177] Kim SY, Herbst A, Tworkowski KA, Salghetti SE, Tansey WP: Skp2 Regulates Myc Protein Stability and Activity. Molecular Cell 2003, 11: 1177-1188.

[178] Yeh KH, Kondo T, Zheng J, Tsvetkov LM, Blair J, Zhang H: The F-Box Protein SKP2 Binds to the Phosphorylated Threonine 380 in Cyclin E and Regulates Ubiquitin-Dependent Degradation of Cyclin E. Biochemical and Biophysical Research Communications 2001, 281: 884-890.

[179] Lonjedo M, Poch E, Mocholí E, Hernández-Sánchez M, Ivorra C, Franke TF, et al.: The Rho Family Member RhoE Interacts with Skp2 and is Degraded at the Proteasome During Cell Cycle Progression. The Journal of Biological Chemistry 2013, 288: 30872-30882.

[180] Méndez J, Zou-Yang XH, Kim SY, Hidaka M, Tansey WP, Stillman B: Human Origin Recognition Complex Large Subunit is Degraded by Ubiquitin-Mediated Proteolysis After Initiation of DNA Replication. Molecular Cell 2002, 9: 481-491.

[181] Kondo T, Kobayashi M, Tanaka J, Yokoyama A, Suzuki S, Kato N, et al.: Rapid Degradation of Cdt1 Upon UV-Induced DNA Damage is Mediated by SCF Skp2 Complex . The Journal of Biological Chemistry 2004, 279: 27315-27319.

[182] Jiang H, Chang FC, Ross AE, Lee J, Nakayama K, Nakayama K, et al.: Ubiquitylation of RAG-2 by Skp2-SCF Links Destruction of the V(D)J Recombinase to the Cell Cycle. Molecular Cell 2005, 18: 699-709.

[183] Liang M, Liang YY, Wrighton K, Ungermannova D, Wang XP, Brunicardi FC, et al.: Ubiquitination and Proteolysis of Cancer-Derived Smad4 Mutants by SCF^Skp2 . Molecular and Cellular Biology 2004, 24: 7524-7537.

[184] Lin YW, Yang JL: Cooperation of ERK and SCF^Skp2 for MKP-1 Destruction Provides a Positive Feedback Regulation of Proliferating Signaling . The Journal of Biological Chemistry 2006, 281: 915-926.

[185] Tokarz S, Berset C, La Rue J, Friedman K, Nakayama K, Nakayama K, et al.: The ISG15 Isopeptidase UBP43 is Regulated by Proteolysis via the SCF^Skp2 Ubiquitin Ligase . The Journal of Biological Chemistry 2004, 279: 46424-46430.

[186] Bellanger S, Tan CL, Nei W, He PP, Thierry F: The Human Papillomavirus Type 18 E2 Protein is a Cell Cycle-Dependent Target of the SCF^Skp2 Ubiquitin Ligase . Journal of Virology 2010, 84: 437-444.

[187] Oh KJ, Kalinina A, Wang J, Nakayama K, Nakayama KI, Bagchi S: The Papillomavirus E7 Oncoprotein is Ubiquitinated by UbcH7 and Cullin 1- and Skp2-Containing E3 Ligase. Journal of Virology 2004, 78: 5338-5346.

[188] Nakayama K, Nagahama H, Minamishima YA, Matsumoto M, Nakamichi I, Kitagawa K, et al.: Targeted Disruption of Skp2 Results in Accumulation of Cyclin E and p27 Kip1, Polyploidy and Centrosome Overduplication . The Embo Journal 2000, 19: 2069-2081.

[189] Galardi S, Mercatelli N, Giorda E, Massalini S, Frajese GV, Ciafrè SA, et al.: miR-221 and miR-222 Expression Affects the Proliferation Potential of Human Prostate Carcinoma Cell Lines by Targeting p27^Kip1 . The Journal of Biological Chemistry 2007, 282: 23716-23724.

[190] Hattori T, Isobe T, Abe K, Kikuchi H, Kitagawa K, Oda T, et al.: Pirh2 Promotes Ubiquitin-Dependent Degradation of the Cyclin-Dependent Kinase Inhibitor p27 Kip1 . Cancer Research 2007, 67: 10789-10795.

[191] Kamura T, Hara T, Matsumoto M, Ishida N, Okumura F, Hatakeyama S, et al.: Cytoplasmic Ubiquitin Ligase KPC Regulates Proteolysis of p27 Kip1 at G1 Phase . Nature Cell Biology 2004, 6: 1229-1235.

[192] Hara T, Kamura T, Kotoshiba S, Takahashi H, Fujiwara K, Onoyama I, et al.: Role of the UBL-UBA Protein KPC2 in Degradation of p27 at G1 Phase of the Cell Cycle. Molecular and Cellular Biology 2005, 25: 9292-9303.

[193] Yu X, Wang R, Zhang Y, Zhou L, Wang W, Liu H, et al.: Skp2-Mediated Ubiquitination and Mitochondrial Localization of Akt drive Tumor Growth and Chemoresistance to Cisplatin. Oncogene 2019, 38: 7457-7472.

[194] Yao F, Zhou Z, Kim J, Hang Q, Xiao Z, Ton BN, et al.: SKP2-and OTUD1-Regulated Non-Proteolytic Ubiquitination of YAP Promotes YAP Nuclear Localization and Activity. Nature Communications 2018, 9: 2269.

[195] Lee SW, Li CF, Jin G, Cai Z, Han F, Chan CH, et al.: Skp2-Dependent Ubiquitination and Activation of LKB1 is Essential for Cancer Cell Survival Under Energy Stress. Molecular Cell 2015, 57: 1022-1033.

[196] Wang JY, Liu GZ, Wilmott JS, La T, Feng YC, Yari H, et al.: Skp2-Mediated Stabilization of MTH1 Promotes Survival of Melanoma Cells upon Oxidative Stress. Cancer Research 2017, 77: 6226-6239.

[197] Wu J, Zhang X, Zhang L, Wu CY, Rezaeian AH, Chan CH, et al.: Skp2 E3 Ligase Integrates ATM Activation and Homologous Recombination Repair by Ubiquitinating NBS1. Molecular Cell 2012, 46: 351-361.

[198] Gao D, Inuzuka H, Tseng A, Wei W: Akt Finds its New Path to Regulate Cell Cycle Through Modulating Skp2 Activity and its Destruction by APC/Cdh1. Cell Division 2009, 4: 11.

[199] Rezaeian AH, Phan LM, Zhou X, Wei W, Inuzuka H: Pharmacological Inhibition of the SKP2/p300 Signaling Axis Restricts Castration-Resistant Prostate Cancer. Neoplasia 2023, 38: 100890.

[200] Neary CL, Pastorino JG: Akt Inhibition Promotes Hexokinase 2 Redistribution and Glucose Uptake in Cancer Cells. Journal of Cellular Physiology 2013, 228: 1943-1948.

[201] Wieman HL, Wofford JA, Rathmell JC: Cytokine Stimulation Promotes Glucose Uptake via Phosphatidylinositol-3 Kinase/Akt Regulation of Glut1 Activity and Trafficking. Molecular Biology of the Cell 2007, 18: 1437-1446.

[202] Ahn E, Kumar P, Mukha D, Tzur A, Shlomi T: Temporal Fluxomics Reveals Oscillations in TCA Cycle Flux Throughout the Mammalian Cell Cycle. Molecular Systems Biology 2017, 13: 953.

[203] Liu J, Peng Y, Wei W: Cell Cycle on the Crossroad of Tumorigenesis and Cancer Therapy. Trends in Cell Biology 2022, 32: 30-44.

[204] Zhang S, Chen Q, Liu Q, Li Y, Sun X, Hong L, et al.: Hippo Signaling Suppresses Cell Ploidy and Tumorigenesis Through Skp2. Cancer Cell 2017, 31: 669-684.e7.

[205] von der Lehr N, Johansson S, Wu S, Bahram F, Castell A, Cetinkaya C, et al.: The F-box Protein Skp2 Participates in c-Myc Proteosomal Degradation and Acts as a Cofactor for c-Myc-Regulated Transcription. Molecular Cell 2003, 11: 1189-1200.

[206] Chen Y, Sun XX, Sears RC, Dai MS: Writing and Erasing MYC Ubiquitination and SUMOylation. Genes & Diseases 2019, 6: 359-371.

[207] Lv L, Miao Q, Zhan S, Chen P, Liu W, Lv J, et al.: LKB1 Dictates Sensitivity to Immunotherapy Through Skp2-Mediated Ubiquitination of PD-L1 Protein in Non-Small Cell Lung Cancer . Journal for Immunotherapy of Cancer 2024, 12: e009444.

[208] Li Z, Wan J, Li S, Tang Y, Lin YC, Ni J, et al.: Multi-Omics Characterization of E3 Regulatory Patterns in Different Cancer Types. International Journal of Molecular Sciences 2024; 25: 7639.

[209] Wang Z, Fukushima H, Inuzuka H, Wan L, Liu P, Gao D, et al.: Skp2 is a Promising Therapeutic Target in Breast Cancer. Frontiers in Oncology 2012, 1: 57.

[210] Lord CJ, Ashworth A: PARP Inhibitors: Synthetic Lethality in the Clinic. Science 2017, 355: 1152-1158.

[211] Ray Chaudhuri A, Nussenzweig A: The Multifaceted Roles of PARP1 in DNA Repair and Chromatin Remodelling. Nature Reviews Molecular Cell Biology 2017, 18: 610-621.

[212] Haince JF, McDonald D, Rodrigue A, Déry U, Masson JY, Hendzel MJ, et al.: PARP1-Dependent Kinetics of Recruitment of MRE11 and NBS1 Proteins to Multiple DNA Damage Sites. Journal of Biological Chemistry 2008, 283: 1197-1208.

[213] Ray Chaudhuri A, Callen E, Ding X, Gogola E, Duarte AA, Lee JE, et al.: Replication Fork Stability Confers Chemoresistance in BRCA-Deficient Cells . Nature 2016, 535: 382-387.

[214] Saini S, Hirata H, Majid S, Dahiya R: Functional Significance of Cytochrome P450 1B1 in Endometrial Carcinogenesis . Cancer Research 2009, 69: 7038-7045.

[215] Peng Y, Qi X, Ding L, Huang J, Liu Y, Zheng R, et al.: SKP2 Inhibition Activates Tumor Cell-Intrinsic Immunity by Inducing DNA Replication Stress and Genomic Instability. British Journal of Cancer 2025, 132: 81-92.

[216] Wang Z, Zhang Y, Liu J, Wang D, Wang S, Xie Z: Skp2 Targets the Androgen Receptor for Degradation to Regulate Prostate Cancer Cell Survival and Proliferation. Biochemical and Biophysical Research Communications 2014, 450: 1335-1341.

[217] Wang X, Wang J, Jin F: Identification of Skp2 as a Novel Target of the Akt/mTOR Pathway in Prostate Cancer. International Journal of Oncology 2012, 41: 1289-1296.

[218] Shimura H, Shimura-Miura H, Kuwano M, Harper JW, Nakayama KI: Skp2 is Required for Skp2-Mediated Degradation of p27 and Prostate Cancer Development in the TRAMP Model. Cancer Research 2003, 63: 186-190.

[219] Shigemasa K, Gu L, Tanimoto H, Oue N, Yasui W, Hamura T: Skp2 Regulates Twist Expression and Promotes Epithelial-Mesenchymal Transition in Human Prostate Cancer Cells. Molecular Carcinogenesis 2013, 52: 11-19.

[220] Shi C, Zhang Z, Shi Z, Wang S, Furuya T, Lin H, et al.: Skp2 Stabilizes Twist to Promote Proliferation and Migration of Prostate Cancer Cells. Molecular Cancer Research 2014, 12: 1178-1187.

[221] Yang G, Ayala G, De Marzo A, Tian W, Frolov A, Wheeler TM, et al.: Elevated Skp2 Protein Expression in Human Prostate Cancer: Association with High Histologic Grade and Reduced Patient Survival. Cancer Research 2002, 62: 2583-2589.

[222] Wang Z, Zhang Y, Liu J, Wang D, Wang S, Xie Z: Skp2: A Novel Potential Therapeutic Target for Prostate Cancer. Biochimica et Biophysica Acta 2016, 1866: 207-218.

[223] Li B, Niu A, Wu Z: Down-Regulation of Skp2 Expression Inhibits Invasion and Induces Apoptosis in Human Breast Cancer Cells. Pathology & Oncology Research 2014, 20: 67-73.

[224] Ning N, Liu S, Liu X, Tian Z, Jiang Y, Yu N, et al.: Curcumol Suppresses Breast Cancer Cell Metastasis by Inhibiting Skp2-Mediated Bim Degradation . Oncology Reports 2016, 36: 3505-3511.

[225] Clement E, Inuzuka H, Nihira NT, Wei W, Toker A: Skp2 Dictates Cell Cycle Progression and Therapeutic Resistance in Triple-Negative Breast Cancer. Cancer Research 2018, 78: 3165-3175.

[226] Wang X, Yang L, Huang F, Zhang Q, Liu S, Li L: Targeting the Skp2-PD-L1 Axis for Cancer Immunotherapy. Trends in Cancer 2019, 5: 12-15.

[227] Zhang H, Sun L, Liang J, Yu Z, Jin Y: Skp2 Regulates Non-Small Cell Lung Cancer Cell Growth and Sensitivity to Gefitinib. Oncology Reports 2015, 34: 2479-2486.

[228] Lim SO, Li CW, Xia W, Cha JH, Chan LC, Tanaka T, et al.: Glycosylation-Dependent PD-L1 Accumulation for Poor Clinical Outcome in Lung Cancer. Molecular Cell 2016, 62: 390-402.

[229] Yu H, Zhao T, Liu Z: Prognostic Value of Skp2 Expression in Patients with Non-Small Cell Lung Cancer: A Meta-Analysis. World Journal of Surgical Oncology 2015, 13: 33.

[230] Gu C, Wang D, Liu J, Chen Z: Targeting the Skp2-p27 Axis in Multiple Myeloma. Blood 2012, 119: 535-536.

[231] Li Z, Liu S, Sun J, Li X: A Novel Small-Molecule Inhibitor of Skp2-Mediated Ubiquitin-Proteasome System (UPS) Induces Apoptosis in Multiple Myeloma. Leukemia & Lymphoma 2014, 55: 115-123.

[232] Katagiri S, Tauchi T, Okabe S, Sashida G, Ohyashiki K: Mblockade of the Ubiquitin-Proteasome Pathway Inhibits the Expression of Maf and Myc and Induces Cell Death in Multiple Myeloma. Annals of Hematology 2015, 94: 1545-1553.

[233] Andreu EJ, Lledo E, Pocovi M: The BCR-ABL Inhibitor Imatinib Suppresses Skp2 Expression and Promotes p27^Kip1 Accumulation in Chronic Myelogenous Leukemia Cells . Cancer Research 2005, 65: 3264-3272.

[234] Wei Z, Jiang X, Qiao H, Zhai B, Zhang L, Zhang Q, et al.: Skp2 Overexpression is Associated with Poor Prognosis and 5-Fluorouracil Resistance in Human Colorectal Carcinoma. Journal of Clinical Pathology 2015, 68: 962-968.

[235] Calvisi DF, Ladu S, Conner EA, Seo D, Heyer J, Factor VM, et al.: Skp2 Drives the Ubiquitylation and Degradation of LKB1 and Regulates Hepatocellular Carcinoma Progression. Cancer Research 2011, 71: 3332-3343.

[236] Calvisi DF, Ladu S, Pinna F, Frau M, Tomasi ML, Sini M, et al.: SKP2 and CKS1 promote degradation of cell cycle regulators and are associated with hepatocellular carcinoma prognosis. Gastroenterology 2009, 137: 1816-26.e1-10.

[237] Kan G, Wang Z, Ma Q, Chen C, Li X: CD147 Promotes Src-Dependent Activation of Skp2 to Enhance Nrf2 Stability and Temozolomide Resistance in Glioblastoma. Cell Death & Disease 2015, 6: e1918.

[238] Zhang S, Mercado-Uribe I, Liu J: Polyploid Giant Cancer Cells: The “Root” of Tumor Recurrence and Drug Resistance. Seminars in Cancer Biology 2022, 81: 109-119.

[239] Lv C, Hong Y, Miao L, Li C: Skp2 Regulates Polyploidy Formation in Ovarian Cancer Cells. Oncology Letters 2020, 19: 1255-1262.

[240] Gad H, Koolmeister T, Jemth AS, Eshtad S, Jacques SA, Strom CE, et al.: MTH1 Inhibition Kills Cancer by Preventing Sanitation of the dNTP Pool. Nature 2014, 508: 215-221.

[241] Tu Y, Chen C, Pan W, Xu M, Zhai Y: Epigenetic Silencing of MTH1 Promotes Cell Cycle Arrest and Apoptosis in Human Malignant Melanoma. Carcinogenesis 2012, 33: 1480-1488.

[242] Li B, Lu W, Yang Q, Yu X, Matusik RJ, Chen Z: Skp2 Regulates Androgen Receptor Through Ubiquitin-Mediated Degradation Independent of Akt/mTOR Pathways in Prostate Cancer. The Prostate 2014, 74: 421-432.

[243] Zhu CQ, Blackhall FH, Pintilie M, Iyengar P, Liu N, Ho J, et al.: Skp2 Gene Copy Number Aberrations are Common in Non-Small Cell Lung Carcinoma, and its Overexpression in Tumors with Ras Mutation is a Poor Prognostic Marker . Clinical Cancer Research 2004, 10: 1984-1991.

[244] Yu X, Zhou L, Liu W, Liu L, Gao F, Li W, et al.: Skp2 Stabilizes Mcl-1 and Confers Radioresistance in Colorectal Cancer. Cell Death & Disease 2022, 13: 249.

[245] William JNG, Dhar R, Gundamaraju R, Sahoo OS, Pethusamy K, Raj AFPAM, et al.: SKping Cell Cycle Regulation: Role of Ubiquitin Ligase SKP2 in Hematological Malignancies. Frontiers in Oncology 2024, 14: 1288501.

[246] Aguirre-Ghiso JA: Models, Mechanisms and Clinical Evidence for Cancer Dormancy. Nature Reviews Cancer 2007, 7: 834-846.

[247] Besson A, Dowdy SF, Roberts JM: CDK Inhibitors: Cell Cycle Regulators and Beyond. Developmental Cell 2008, 14: 159-169.

[248] Slingerland J, Pagano M: Regulation of the Cdk Inhibitor p27 and its Deregulation in Cancer. Journal of Cellular Physiology 2000, 183: 10-17.

[249] Elfoly M, Mirza JY, Alaiya A, Al-Hazzani AA, Tulbah A, Al-Alwan M, et al.: PD-L1 Intrinsically Promotes the Proliferation of Breast Cancer Cells Through the SKP2-p27/p21 Axis. Cancer Cell International 2024, 24: 161.

[250] Porcelli G, D’Accardo C, Angeloro F, Cucchiara M, Bianca P, Pantina VD, et al.: Decoding Cancer Dormancy: Integrative Genomic, Phenotypic and Live-Cell Imaging Analysis to Reveal the Hidden Cancer Cell Reservoir. Molecular Cancer 2025, 24: 286.

[251] Murata S, Zhang C, Finch N, Zhang K, Campo L, Breuer EK: Predictors and Modulators of Synthetic Lethality: An Update on PARP Inhibitors and Personalized Medicine. BioMed Research International 2016, 2016: 2346585.

[252] Agudo J, Aguirre-Ghiso JA, Bhatia M, Chodosh LA, Correia AL, Klein CA: Targeting Cancer Cell Dormancy. Nature Reviews Cancer 2024, 24: 97-104.

[253] Wu T, Gu X, Cui H: Emerging Roles of SKP2 in Cancer Drug Resistance. Cells 2021, 10: 1147.

[254] Yang G, Ayala G, De Marzo A, Tian W, Frolov A, Wheeler TM, et al.: Elevated Skp2 Protein Expression in Human Prostate Cancer: Association with Loss of the Cyclin-Dependent Kinase Inhibitor p27 and PTEN and with Reduced Recurrence-Free Survival. Clinical Cancer Research 2002, 8: 3419-3426.

[255] Šimečková Š, Kahounová Z, Fedr R, Remšík J, Slabáková E, Suchánková T, et al.: High Skp2 Expression is Associated with a Mesenchymal Phenotype and Increased Tumorigenic Potential of Prostate Cancer Cells. Scientific Reports 2019, 9: 5695.

[256] Li CL, Huang CW, Ko CJ, Fang SY, Ou-Yang FU, Pan MR, et al.: Curcumol Suppresses Triple-Negative Breast Cancer Metastasis by Attenuating Anoikis Resistance via Inhibition of Skp2-Mediated Transcriptional Addiction. Anticancer Research 2020, 40: 5529-5538.

[257] Zhong K, Yang F, Han Q, Chen J, Wang J: Skp2 Expression has Different Clinicopathological and Prognostic Implications in Lung Adenocarcinoma and Squamous Cell Carcinoma . Oncology Letters 2018, 16: 2873-2880.

[258] Yokoi S, Yasui K, Mori M, Iizasa T, Fujisawa T, Inazawa J: Amplification and Overexpression of SKP2 are Associated with Metastasis of Non-Small-Cell Lung Cancers to Lymph Nodes . The American Journal of Pathology 2004, 165: 175-180.

[259] Takanami I: The Prognostic Value of Overexpression of Skp2 mRNA in Non-Small Cell Lung Cancer. Oncology Reports 2005, 13: 727-731.

[260] Zhou H, Zhou L, Guan Q, Hou X, Wang C, Liu L, et al.: Skp2-Mediated MLKL Degradation Confers Cisplatin-Resistant in Non-Small Cell Lung Cancer Cells. Communications Biology 2023, 6: 805.

[261] Faruq O, Ngo J, Iyer D, Nesson J, Shrestha M, Chang H: Targeting of SKP2 to Combat Drug Resistance in Multiple Myeloma . Scientific Reports 2025, 15: 37838.

[262] Malek E, Abdel-Malek MA, Jagannathan S, Vad N, Karns R, Jegga AG, et al.: Pharmacogenomics and Chemical Library Screens Reveal a Novel SCF^SKP2 Inhibitor that Overcomes Bortezomib Resistance in Multiple Myeloma . Leukemia 2017, 31: 645-653.

[263] Andreu EJ, Lledó E, Poch E, Ivorra C, Albero MP, Martínez-Climent JA, et al.: BCR-ABL Induces the Expression of Skp2 through the PI3K Pathway to Promote p27^Kip1 Degradation and Proliferation of Chronic Myelogenous Leukemia Cells . Cancer Research 2005, 65: 3264-3272.

[264] Chen X, Huang Z, Wu W, Xia R: Inhibition of Skp2 Sensitizes Chronic Myeloid Leukemia Cells to Imatinib. Cancer Management and Research 2020, 12: 4777-4787.

[265] Dong X, Li K, Wang R, Wei B, Li Y, Zhang Y, et al.: Targeting Skp2 by Tanshinone IIA Overcomes Chemoresistance in Colorectal Cancer. Cell Biology and Toxicology 2025, 41: 135.

[266] Delogu S, Wang C, Cigliano A, Utpatel K, Sini M, Longerich T, et al.: SKP2 Cooperates with N-Ras or AKT to Induce Liver Tumor Development in Mice. Oncotarget 2015, 6: 2222-2234.

[267] Li J, Zhao L, Wu Z, Huang S, Wang J, Chang Y, et al.: SelK Promotes Glioblastoma Cell Proliferation by Inhibiting β-TrCP1 Mediated Ubiquitin-Dependent Degradation of CDK4. Journal of Experimental & Clinical Cancer Research 2024, 43: 231.

[268] Lv H, Shi Y, Zhang L, Zhang D, Liu G, Yang Z, et al.: Polyploid Giant Cancer Cells with Budding and the Expression of Cyclin E, S-phase Kinase-Associated Protein 2, Stathmin Associated with the Grading and Metastasis in Serous Ovarian Tumor. BMC Cancer 2014, 14: 576.

[269] Zhang S, Mercado-Uribe I, Xing Z, Sun B, Kuang J, Liu J: Generation of Cancer Stem-Like Cells through the Formation of Polyploid Giant Cancer Cells. Oncogene 2014, 33: 116-128.

[270] Chen T, Liu L, Zou Y, Hu X, Zhang W, Zhou T, et al.: Nobiletin Downregulates the SKP2-p21/p27-CDK2 Axis to Inhibit Tumor Progression and Shows Synergistic Effects with Palbociclib on Renal Cell Carcinoma. Cancer Biology & Medicine 2021, 18: 227-244.

[271] Masuda TA, Inoue H, Sonoda H, Mine S, Yoshikawa Y, Nakayama K, et al.: Clinical and Biological Significance of S-phase Kinase-associated Protein 2 (Skp2) Gene Expression in Gastric Carcinoma: Modulation of Malignant Phenotype by Skp2 Overexpression, Possibly via p27 Proteolysis. Cancer Research 2002, 62: 3819-3825.

[272] Einama T, Kagata Y, Tsuda H, Morita D, Ogata S, Ueda S, et al.: High-Level Skp2 Expression in Pancreatic Ductal Adenocarcinoma: Correlation with the Extent of Lymph Node Metastasis, Higher Histological Grade, and Poorer Patient Outcome. Pancreas 2006, 32: 376-381.

[273] Wang J, Huang Y, Guan Z, Zhang JL, Su HK, Zhang W, et al.: E3-Ligase Skp2 Predicts Poor Prognosis and Maintains Cancer Stem Cell Pool in Nasopharyngeal Carcinoma. Oncotarget 2014, 5: 5591-5601.

[274] Liao X, Zhang Y, Yu X, Du W, Chen L, Zhao Z, et al.: A Pan-Cancer Analysis Revealed SKP2 as an Inhibitor of the Tumor Immune Microenvironment and a Promising Therapeutic Target for Immunotherapy . Precision Clinical Medicine 2025, 8: pbaf022.

[275] Tan S, Wang R, Fang J, Yi M, Guo P, Han S, et al.: E3 Ligase Skp2-Mediated Stabilization of Survivin Contributes to Radioresistance. Cell Death Discovery 2025, 11: 151.

[276] Oliveira AM, Okuno SH, Nascimento AG, Lloyd RV: Skp2 Protein Expression in Soft Tissue Sarcomas. Journal of Clinical Oncology 2003, 21: 722-727.

[277] Bonda DJ, Lee HP, Kudo W, Zhu X, Smith MA, Lee HG: Lee. Pathological Implications of Cell Cycle Re-entry in Alzheimer Disease. Expert Reviews in Molecular Medicine 2010, 12: e19.

[278] García-Osta A, Dong J, Moreno-Aliaga MJ, Ramirez MJ: p27, The Cell Cycle and Alzheimer’s Disease. International Journal of Molecular Sciences 2022, 23: 1211.

[279] Fishman-Jacob T, Youdim MBH: A Sporadic Parkinson’s Disease Model via Silencing of the Ubiquitin-Proteasome/E3 Ligase Component, SKP1A. Journal of Neural Transmission (Vienna, Austria: 1996) 2024, 131: 675-707.

[280] Di Fonzo A, Dekker MC, Montagna P, Baruzzi A, Yonova EH, Correia Guedes L, et al.: FBXO7 Mutations Cause Autosomal Recessive, Early-Onset Parkinsonian-Pyramidal Syndrome. Neurology 2009, 72: 240-245.

[281] Burchell VS, Nelson DE, Sanchez-Martinez A, Delgado-Camprubi M, Ivatt RM, Pogson JH, et al.: The Parkinson’s Disease-Linked Proteins Fbxo7 and Parkin Interact to Mediate Mitophagy. Nature Neuroscience 2013, 16: 1257-1265.

[282] Lin HK, Chen Z, Wang G, Nardella C, Lee SW, Chan CH, et al.: Skp2 Targeting Suppresses Tumorigenesis by Arf-p53-Independent Cellular Senescence . Nature 2010, 464: 374-379.

[283] Galdeano C: Drugging the Undruggable: Targeting Challenging E3 Ligases for Personalized Medicine. Future Medicinal Chemistry 2017, 9: 347-350.

[284] Wu L, Grigoryan AV, Li Y, Hao B, Pagano M, Cardozo TJ: Specific Small Molecule Inhibitors of Skp2-Mediated p27 Degradation. Chemistry & Biology 2012, 19: 1515-1524.

[285] Ungermannova D, Lee J, Zhang G, Dallmann HG, McHenry CS, Liu X: High-Throughput Screening AlphaScreen Assay for Identification of Small-Molecule Inhibitors of Ubiquitin E3 Ligase SCF^Skp2-Cks1 . Journal of Biomolecular Screening 2013, 18: 910-920.

[286] Rico-Bautista E, Zhu W, Kitada S, Ganapathy S, Lau E, Krajewski S, et al.: Small Molecule-Induced Mitochondrial Disruption Directs Prostate Cancer Inhibition via UPR Signaling. Oncotarget 2013, 4: 1212-1229.

[287] Li X, Yokoyama NN, Zhang S, Ding L, Liu HM, Lilly MB, et al.: Flavokawain A Induces deNEDDylation and Skp2 Degradation Leading to Inhibition of Tumorigenesis and Cancer Progression in the TRAMP Transgenic Mouse Model. Oncotarget 2015, 6: 41809-41824.

[288] Liang H, Zhang F, Hong Y, Wu Y, Xie H, Zhang C, et al.: Synergistic Silencing of Skp2 by siRNA Self-Assembled Nanoparticles as a Therapeutic Strategy for Advanced Prostate Cancer. Small (Weinheim an der Bergstrasse, Germany) 2022, 18: e2106046.

[289] Bigdeli M, Tremblay E, Provencher D, Mes-Masson AM, Rodier F: Exploiting Synthetic Lethality in Epithelial Ovarian Cancer: Multi-Dimensional Approaches Beyond DNA Damage Repair. Molecular Cancer 2026. doi: 10.1186/s12943-025-02562-w

[290] Blackford AN, Jackson SP: ATM, ATR, and DNA-PK: The Trinity at the Heart of the DNA Damage Response. Molecular Cell 2017, 66: 801-817.

[291] Mateo J, Lord CJ, Serra V, Tutt A, Balmaña J, Castroviejo-Bermejo M, et al.: A Decade of Clinical Development of PARP Inhibitors in Perspective. Annals of Oncology 2019, 30: 1437-1447.

[292] Jing J, Rui L, Junyuan S, Jinfeng Y, Zhihao H, Weiguo L, et al.: Small-Molecule Compounds Inhibiting S-phase Kinase-Associated Protein 2: A Review. Frontiers in Pharmacology 2023, 14: 1122008.

[293] Zhu L: Skp2 Knockout Reduces Cell Proliferation and Mouse Body Size: and Prevents Cancer? Cell Research 2010, 20: 605-607.

[294] Rodríguez-Gimeno A, Galdeano C: Drug Discovery Approaches to Target E3 Ligases. Chembiochem 2025, 26: e202400656.

[295] Lough L, Sherman D, Ni E, Young LM, Hao B, Cardozo T: Chemical Probes of Skp2-Mediated p27 Ubiquitylation and Degradation. Medchemcomm 2018, 9: 1093-1104.

[296] Dong G, Huang A, Zhao Z, Lai B, Pan X, Yang H, et al.: Discovery of SKP2-Recruiting PROTACs for Target Protein Degradation. Advanced Science (Weinh) 2026: e15159.

[297] Radhakrishnan S, Hoff O, Muellner MK: Current Challenges in Small Molecule Proximity-Inducing Compound Development for Targeted Protein Degradation Using the Ubiquitin Proteasomal System. Molecules 2022, 27: 8119.

[298] Feng T, Wang P, Zhang X: Skp2: A Critical Molecule for Ubiquitination and its Role in Cancer. Life Sciences 2024, 338: 122409.

[299] Gstaiger M, Jordan R, Lim M, Catzavelos C, Mestan J, Slingerland J, et al.: Skp2 is Oncogenic and Overexpressed in Human Cancers. Proceedings of the National Academy of Sciences of the United States of America 2001, 98: 5043-5048.

[300] Mi D, Huang A, Song J, Chen Y: A Long March for Targeted Protein Degradation in the New Era: Expanding E3 Ligases. Future Medicinal Chemistry 2024, 16: 2189-2191.

[301] Lee J, Lee Y, Jung YM, Park JH, Yoo HS, Park J: Discovery of E3 Ligase Ligands for Target Protein Degradation. Molecules 2022, 27: 6515.

[302] Koseoglu MM, Norambuena A, Sharlow ER, Lazo JS, Bloom GS: Aberrant Neuronal Cell Cycle Re-entry: The Pathological Confluence of Alzheimer’s Disease and Brain Insulin Resistance, and Its Relation to Cancer. Journal of Alzheimer’s Disease: JAD 2019, 67: 1-11.

[303] McCarthy. Without SKP2, Nature Reviews Cancer 2010, 10: 314- 314.

[304] Neudorf NM, Thompson LL, Lichtensztejn Z, Razi T, McManus KJ: Reduced SKP2 Expression Adversely Impacts Genome Stability and Promotes Cellular Transformation in Colonic Epithelial Cells . Cells 2022, 11: 3731.

[305] Jiang X, Li Y, Feng JL, Nik Nabil WN, Wu R, Lu Y, et al.: Safrana l Prevents Prostate Cancer Recurrence by Blocking the Re-activation of Quiescent Cancer Cells via Downregulation of S-phase Kinase-Associated Protein 2. Frontiers in Cell and Developmental Biology 2020, 8: 598620.

[306] Chen X, Zhou J, Dong X, Xu Y, Chen B: Regulatory Role of E3 Ubiquitin Ligases in Multiple Myeloma: From Molecular Mechanisms to Therapeutic Strategies. Frontiers in Cell and Developmental Biology 2025, 13: 1620097.