Background: Chemotherapy resistance remains a critical hurdle in advanced prostate cancer (PCa). Succinylation, an essential post-translational modification linking cellular metabolism with epigenetic regulation, has been implicated in tumour progression; however, its contribution to PCa chemoresistance remains poorly defined.
Objective: This study aimed to evaluate the prognostic significance of succinylation in PCa, develop a succinylation-based biomarker, and elucidate the mechanisms driving chemotherapy resistance.
Methods: We generated a succinylation score (SS) by applying single-sample gene set enrichment analysis (ssGSEA) to transcriptomic profiles from the TCGA-PRAD cohort. Its relationships with survival, the tumour microenvironment (TME), and treatment susceptibility were examined using CIBERSORT, GSEA, TIDE, oncoPredict, and single-cell RNA sequencing (scRNA-seq). Findings were functionally validated in patient-derived organoids, PCa cell lines, and xenograft models through genetic manipulation, chemosensitivity assays, and mechanistic studies.
Results: High SS correlated with favourable prognosis, lower Gleason scores, absent lymph node metastasis, and an immune-active TME enriched in CD8+ precursor exhausted T cells. High-SS tumours showed enhanced sensitivity to docetaxel and cisplatin. scRNA-seq identified KAT2A as a key driver in low-SS malignant clusters with chemoresistance features. KAT2A was elevated in chemoresistant tissues, cell lines, and organoids. KAT2A knockout sensitised cells to chemotherapy, while ectopic expression promoted resistance in vitro and in vivo. Mechanistically, KAT2A-mediated succinylation of PIK3R2 at K477 and K564 inhibited its ubiquitination and proteasomal degradation, stabilising PIK3R2 to drive chemoresistance. The KAT2A inhibitor Butyrolactone 3 synergised with standard chemotherapy to suppress tumour growth.
Conclusion: The succinylation score serves as a robust prognostic biomarker integrating metabolic and immunological features in PCa. The KAT2A-PIK3R2 succinylation pathway represents a newly defined driver of chemoresistance and points to MB-3-based combination therapy as a potential strategy for resistant advanced disease.
| [1] |
Kratzer TB, Mazzitelli N, Star J, Dahut WL, Jemal A, Siegel RL. Prostate Cancer Statistics, 2025. CA Cancer J Clin. 2025; 75(6): 485-497.
|
| [2] |
Lycken M, Bergengren O, Drevin L, et al. Changes in characteristics of men with lethal prostate cancer during the past 25 years: description of population-based deaths. Eur Urol Open Sci. 2022; 41: 81-87.
|
| [3] |
Min Y, Wei X, Chen H, Xiang K, Yin G, Feng Y. Identifying clinicopathological risk factors of the regional lymph node metastasis in patients with T(1-2) mucinous breast cancer: a population-based study. J Oncol. 2021; 2021:3866907.
|
| [4] |
Lu J, Zou Q, Li Y, et al. Fth1p8 induces and transmits docetaxel resistance by inhibiting ferroptosis in prostate cancer. Biomed Pharmacother. 2024; 180:117472.
|
| [5] |
Wu T, Zhao Y, Zhang X, et al. Short-chain acyl post-translational modifications in cancers: mechanisms, roles, and therapeutic implications. Cancer Commun (Lond). 2025; 45(10): 1247-1284.
|
| [6] |
He S, Wang C, Li R, et al. The role of succinylation-mediated metabolic reprogramming in tumor progression. Mol Biol Rep. 2025; 52(1): 954.
|
| [7] |
Lu K, Han D. A review of the mechanism of succinylation in cancer. Medicine (Baltimore). 2022; 101(45):e31493.
|
| [8] |
Rardin MJ, He W, Nishida Y, et al. Sirt5 regulates the mitochondrial lysine succinylome and metabolic networks. Cell Metab. 2013; 18(6): 920-933.
|
| [9] |
Shen R, Ruan H, Lin S, et al. Lysine succinylation, the metabolic bridge between cancer and immunity. Genes Dis. 2023; 10(6): 2470-2478.
|
| [10] |
Zhang N, Sun L, Zhou S, et al. Cholangiocarcinoma Pdha1 succinylation suppresses macrophage antigen presentation via alpha-ketoglutaric acid accumulation. Nature Communications. 2025; 16(1): 3177.
|
| [11] |
C H Chang, Qiu J, O'Sullivan D, et al. Metabolic competition in the tumor microenvironment is a driver of cancer progression. Cell. 2015; 162(6): 1229-1241.
|
| [12] |
Zou W, Green DR. Beggars Banquet: metabolism in the tumor immune microenvironment and cancer therapy. Cell Metab. 2023; 35(7): 1101-1113.
|
| [13] |
Chen X, Chen S, Yu D. metabolic reprogramming of chemoresistant cancer cells and the potential significance of metabolic regulation in the reversal of cancer chemoresistance. Metabolites. 2020; 10(7): 289.
|
| [14] |
Ren X, Wang X, Zheng G, et al. Targeting one-carbon metabolism for cancer immunotherapy. Clin Transl Med. 2024; 14(1):e1521.
|
| [15] |
Kwon OK, Bang IH, Choi SY, et al. Ldha desuccinylase Sirtuin 5 as a novel cancer metastatic stimulator in aggressive prostate cancer. Genomics Proteomics Bioinformatics. 2023; 21(1): 177-189.
|
| [16] |
Pujana-Vaquerizo M, Bozal-Basterra L, Carracedo A. Metabolic adaptations in prostate cancer. Br J Cancer. 2024; 131(8): 1250-1262.
|
| [17] |
Zhang W, Meng Y, Liu N, Wen XF, Yang T. Insights into chemoresistance of prostate cancer. Int J Biol Sci. 2015; 11(10): 1160-1170.
|
| [18] |
Dong B, Miao J, Wang Y, et al. Single-cell analysis supports a luminal-neuroendocrine transdifferentiation in human prostate cancer. Commun Biol. 2020; 3(1): 778.
|
| [19] |
Butler A, Hoffman P, Smibert P, Papalexi E, Satija R. Integrating Single-cell transcriptomic data across different conditions, technologies, and species. Nat Biotechnol. 2018; 36(5): 411-420.
|
| [20] |
Stuart T, Butler A, Hoffman P, et al. Comprehensive integration of single-cell data. Cell. 2019; 177(7): 1888-1902 e21.
|
| [21] |
Korsunsky I, Millard N, Fan J, et al. Fast, sensitive and accurate integration of single-cell data with harmony. Nat Methods. 2019; 16(12): 1289-1296.
|
| [22] |
Ritchie ME, Phipson B, Wu D, et al. limma powers differential expression analyses for RNA-sequencing and microarray studies. Nucleic Acids Res. 2015; 43(7): e47.
|
| [23] |
Jiang P, Gu S, Pan D, et al. Signatures of T cell dysfunction and exclusion predict cancer immunotherapy response. Nat Med. 2018; 24(10): 1550-1558.
|
| [24] |
Maeser D, Gruener RF, Huang RS. Oncopredict: an R package for predicting in vivo or cancer patient drug response and biomarkers from cell line screening data. Brief Bioinform. 2021; 22(6):bbab260.
|
| [25] |
Wang P, Henning SM, Magyar CE, Elshimali Y, Heber D, Vadgama JV. Green tea and quercetin sensitize PC-3 xenograft prostate tumors to docetaxel chemotherapy. J Exp Clin Cancer Res. 2016; 35: 73.
|
| [26] |
Festuccia C, Gravina GL, D'Alessandro AM, et al. Azacitidine improves antitumor effects of docetaxel and cisplatin in aggressive prostate cancer models. Endocr Relat Cancer. 2009; 16(2): 401-413.
|
| [27] |
Zhang Y, Gao Y, Ding Y, et al. Targeting Kat2a inhibits inflammatory macrophage activation and rheumatoid arthritis through epigenetic and metabolic reprogramming. MedComm (2020). 2023; 4(3):e306.
|
| [28] |
Zhang Y, Zhang H, Wang H, et al. Tandem mass tag-based quantitative proteomic analysis identification of succinylation related proteins in pathogenesis of thoracic aortic aneurysm and aortic dissection. PeerJ. 2023; 11:e15258.
|
| [29] |
Zhang H, Ling M, Zhang Y, Fang Q, Wo W, Lv X. Oxct1 promotes triple negative breast cancer immune escape via modulating succinylation modification of Pgk1. Commun Biol. 2025; 8(1): 1033.
|
| [30] |
He M, Yang Z, Xie L, et al. Rnf167 mediates atypical ubiquitylation and degradation of Rlrs via two distinct proteolytic pathways. Nature Communications. 2025; 16(1): 1920.
|
| [31] |
Li J, Yan C, Wang Y, et al. Gcn5-mediated regulation of pathological cardiac hypertrophy via activation of the Tak1-Jnk/P38 signaling pathway. Cell Death & Disease. 2022; 13(4): 421.
|
| [32] |
Du L, Liu W, Pichiorri F, Rosen ST. Sumoylation inhibition enhances multiple myeloma sensitivity to lenalidomide. Cancer Gene Ther. 2023; 30(4): 567-574.
|
| [33] |
Ou B, Liu Y, Yang X, Xu X, Yan Y, Zhang J. C5aR1-positive neutrophils promote breast cancer glycolysis through WTAP-dependent m6A methylation of ENO1. cell death & disease. 2021; 12(8): 737.
|
| [34] |
Yan J, Chen D, Ye Z, et al. Molecular mechanisms and therapeutic significance of tryptophan metabolism and signaling in cancer. Mol Cancer. 2024; 23(1): 241.
|
| [35] |
Neubert EN, DeRogatis JM, Lewis SA, et al. Hmgb2 regulates the differentiation and stemness of Exhausted Cd8(+) T cells during chronic viral infection and cancer. Nature Communications. 2023; 14(1): 5631.
|
| [36] |
Zou D, Li XC, Chen W. Beyond T-cell subsets: stemness and adaptation redefining immunity and immunotherapy. Cell Mol Immunol. 2025; 22(9): 957-974.
|
| [37] |
Liu S, Li J, Gu L, Wu K, Xing H. Nanoparticles for chemoimmunotherapy against triple-negative breast cancer. Int J Nanomedicine. 2022; 17: 5209-5227.
|
| [38] |
Wang Y, Guo YR, Liu K, et al. Kat2a coupled with the Alpha-Kgdh complex acts as a histone H3 succinyltransferase. Nature. 2017; 552(7684): 273-277.
|
| [39] |
Liu K, Zhang Q, Lan H, et al. Gcn5 potentiates glioma proliferation and invasion via Stat3 and Akt signaling pathways. Int J Mol Sci. 2015; 16(9): 21897-21910.
|
| [40] |
Tong Y, Guo D, Yan D, et al. Kat2a succinyltransferase activity-mediated 14-3-3zeta upregulation promotes beta-catenin stabilization-dependent glycolysis and proliferation of pancreatic carcinoma cells. Cancer Lett. 2020; 469: 1-10.
|
| [41] |
Li H, Li C, Yang LZ, Liu J. Integrative analysis of histone acetyltransferase Kat2a in human cancer. Cancer Biomark. 2023; 38(4): 443-463.
|
| [42] |
White J, Derheimer FA, Jensen-Pergakes K, et al. Histone lysine acetyltransferase inhibitors: an emerging class of drugs for cancer therapy. Trends Pharmacol Sci. 2024; 45(3): 243-254.
|
Rights & permissions
2026 The Author(s). Clinical and Translational Medicine published by John Wiley & Sons Australia, Ltd on behalf of Shanghai Institute of Clinical Bioinformatics.
PDF
(14837KB)
