PARylation of HMGA1 desensitizes esophageal squamous cell carcinoma to olaparib

Abstract

As a chromatin remodelling factor, high mobility group A1 (HMGA1) plays various roles in both physiological and pathological conditions. However, its role in DNA damage response and DNA damage-based chemotherapy remains largely unexplored. In this study, we report the poly ADP-ribosylation (PARylation) of HMGA1 during DNA damage, leading to desensitization of esophageal squamous cell carcinoma (ESCC) cells to the poly(ADP-ribose) polymerase 1 (PARP1) inhibitor, olaparib. We found that HMGA1 accumulates at sites of DNA damage, where it interacts with PARP1 and undergoes PARylation at residues E47 and E50 in its conserved AT-hook domain. This modification enhances the accumulation of Ku70/Ku80 at the site of DNA damage and activates the DNA-dependent protein kinase catalytic subunit, facilitating nonhomologous end-joining repair. In both subcutaneous tumour models and genetically engineered mouse models of in situ esophageal cancer, HMGA1 interference increased tumour sensitivity to olaparib. Moreover, HMGA1 was highly expressed in ESCC tissues and positively correlated with PARP1 levels as well as poor prognosis in ESCC patients. Taken together, these findings reveal a mechanistic link between HMGA1 and PARP1 in regulating cell responses to DNA damage and suggest that targeting HMGA1 could be a promising strategy to increase cancer cell sensitivity to olaparib.

Keywords

chemotherapy sensitivity / DNA damage / ESCC / HMGA1 / Olaparib / PARP1 / PARylation

References

[1] Lagergren J, Lagergren P. Oesophageal cancer. BMJ (Clin Res Ed). 2010; 341: c6280.

[2] Yang YM, Hong P, Xu WW, He QY, Li B. Advances in targeted therapy for esophageal cancer. Signal transduction and targeted therapy. 2020; 5(1): 229.

[3] Li X, Chen L, Luan S, et al. The development and progress of nanomedicine for esophageal cancer diagnosis and treatment. Semin Cancer Biol. 2022; 86(Pt 2): 873-885.

[4] An J, An S, Choi M, Jung JH, Kim B. Natural products for esophageal cancer therapy: from traditional medicine to modern drug discovery. Int J Mol Sci. 2022; 23(21).

[5] Sung H, Ferlay J, Siegel RL, et al. Global Cancer Statistics 2020: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries. CA Cancer J Clin. 2021; 71(3): 209-249.

[6] Liu Z, Su R, Ahsan A, et al. Esophageal squamous cancer from 4NQO-induced mice model: cNV alterations. Int J Mol Sci. 2022; 23(22).

[7] Tian J, Lu Z, Niu S, et al. Aberrant MCM10 SUMOylation induces genomic instability mediated by a genetic variant associated with survival of esophageal squamous cell carcinoma. Clin Transl Med. 2021; 11(6): e485.

[8] Wang C, Tang H, Geng A, et al. Rational combination therapy for hepatocellular carcinoma with PARP1 and DNA-PK inhibitors. Proc Nat Acad Sci USA. 2020; 117(42): 26356-26365.

[9] Fleury H, MacEachern MK, Stiefel CM, et al. The APE2 nuclease is essential for DNA double-strand break repair by microhomology-mediated end joining. Mol Cell. 2023; 83(9): 1429-1445. e1428.

[10] Nickoloff JA. Toward greater precision in cancer radiotherapy. Cancer Res. 2021; 81(12): 3156-3157.

[11] Matsumoto Y. Development and evolution of DNA-dependent protein kinase inhibitors toward cancer therapy. Int J Mol Sci. 2022; 23(8).

[12] Dietlein F, Thelen L, Reinhardt HC. Cancer-specific defects in DNA repair pathways as targets for personalized therapeutic approaches. Trends Genetics 2014; 30(8): 326-339.

[13] Belan O, Sebald M, Adamowicz M, et al. POLQ seals post-replicative ssDNA gaps to maintain genome stability in BRCA-deficient cancer cells. Mol Cell. 2022; 82(24): 4664-4680. e4669.

[14] Alejo S, Palacios BE, Venkata PP, et al. Lysine-specific histone demethylase 1A (KDM1A/LSD1) inhibition attenuates DNA double-strand break repair and augments the efficacy of temozolomide in glioblastoma. Neuro Oncol. 2023; 25(7): 1249-1261.

[15] Fehr AR, Singh SA, Kerr CM, Mukai S, Higashi H, Aikawa M. The impact of PARPs and ADP-ribosylation on inflammation and host-pathogen interactions. Genes Dev. 2020; 34(5-6): 341-359.

[16] Alemasova EE, Lavrik OI. Poly(ADP-ribosyl)ation by PARP1: reaction mechanism and regulatory proteins. Nucleic Acids Res. 2019; 47(8): 3811-3827.

[17] Cropper JD, Alimbetov DS, Brown KTG, et al. PARP1-MGMT complex underpins pathway crosstalk in O(6)-methylguanine repair. J Hematol Oncol. 2022; 15(1): 146.

[18] Caldecott KW. DNA single-strand break repair and human genetic disease. Trends Cell Biol. 2022; 32(9): 733-745.

[19] Huang D, Kraus WL. The expanding universe of PARP1-mediated molecular and therapeutic mechanisms. Mol Cell. 2022; 82(12): 2315-2334.

[20] Yang G, Liu C, Chen SH, et al. Super-resolution imaging identifies PARP1 and the Ku complex acting as DNA double-strand break sensors. Nucleic Acids Res. 2018; 46(7): 3446-3457.

[21] Noordermeer SM, van Attikum H. PARP inhibitor resistance: a tug-of-war in BRCA-mutated cells. Trends Cell Biol. 2019; 29(10): 820-834.

[22] Singh JK, Smith R, Rother MB, et al. Zinc finger protein ZNF384 is an adaptor of Ku to DNA during classical non-homologous end-joining. Nat Commun. 2021; 12(1): 6560.

[23] Fu X, Li P, Zhou Q, et al. Mechanism of PARP inhibitor resistance and potential overcoming strategies. Genes Dis. 2024; 11(1): 306-320.

[24] Ray-Coquard I, Leary A, Pignata S, et al. Olaparib plus bevacizumab first-line maintenance in ovarian cancer: final overall survival results from the PAOLA-1/ENGOT-ov25 trial. Annal Oncol. 2023; 34(8): 681-692.

[25] Liu JF, Brady MF, Matulonis UA, et al. Olaparib with or without cediranib versus platinum-based chemotherapy in recurrent platinum-sensitive ovarian cancer (NRG-GY004): a randomized, open-label, phase III trial. J Clin Oncol. 2022; 40(19): 2138-2147.

[26] Wang LM, Wang P, Chen XM, et al. Thioparib inhibits homologous recombination repair, activates the type I IFN response, and overcomes olaparib resistance. EMBO Mol Med. 2023; 15(3): e16235.

[27] Tang S, Shen Y, Wei X, Shen Z, Lu W, Xu J. Olaparib synergizes with arsenic trioxide by promoting apoptosis and ferroptosis in platinum-resistant ovarian cancer. Cell Death Dis. 2022; 13(9): 826.

[28] Wang W, Zhang X, Fang Y, et al. Case report: olaparib shows satisfactory clinical outcomes against small cell esophageal carcinoma with ATM mutation. Front Oncol. 2022; 12: 808801.

[29] Cecchini M, Cleary JM, Shyr Y, et al. NCI10066: a Phase 1/2 study of olaparib in combination with ramucirumab in previously treated metastatic gastric and gastroesophageal junction adenocarcinoma. Br J Cancer. 2024; 130(3): 476-482.

[30] Kageyama SI, Junyan D, Hojo H, et al. PARP inhibitor olaparib sensitizes esophageal carcinoma cells to fractionated proton irradiation. J Radiat Res (Tokyo). 2020; 61(2): 177-186.

[31] de Haan R, van den Heuvel MM, van Diessen J, et al. Phase I and pharmacologic study of olaparib in combination with high-dose radiotherapy with and without concurrent cisplatin for non-small cell lung cancer. Clinical Cancer Res. 2021; 27(5): 1256-1266.

[32] Li L, Kim JH, Lu W, et al. HMGA1 chromatin regulators induce transcriptional networks involved in GATA2 and proliferation during MPN progression. Blood. 2022; 139(18): 2797-2815.

[33] Wang L, Zhang J, Xia M, Liu C, Zu X, Zhong J. High Mobility group A1 (HMGA1): structure, biological function, and therapeutic potential. Int J Biol Sci. 2022; 18(11): 4414-4431.

[34] Parisi S, Piscitelli S, Passaro F, Russo T. HMGA proteins in stemness and differentiation of embryonic and adult stem cells. Int J Mol Sci. 2020; 21(1).

[35] Hou P, Meng S, Li M, et al. LINC00460/DHX9/IGF2BP2 complex promotes colorectal cancer proliferation and metastasis by mediating HMGA1 mRNA stability depending on m6A modification. J Exp Clin Cancer Res. 2021; 40(1): 52.

[36] Chia L, Wang B, Kim JH, et al. HMGA1 induces FGF19 to drive pancreatic carcinogenesis and stroma formation. J Clin Invest. 2023; 133(6).

[37] Chiefari E, Foti DP, Sgarra R, et al. Transcriptional regulation of glucose metabolism: the emerging role of the HMGA1 chromatin factor. Front Endocrinol. 2018; 9: 357.

[38] Wang J, Lv B, Su Y, Wang X, Bu J, Yao L. Exosome-mediated transfer of lncRNA HOTTIP promotes cisplatin resistance in gastric cancer cells by regulating HMGA1/miR-218 axis. OncoTargets Ther. 2019; 12: 11325-11338.

[39] Charbonnel C, Rymarenko O, Da Ines O, et al. The Linker Histone GH1-HMGA1 is involved in telomere stability and DNA damage repair. Plant Physiol. 2018; 177(1): 311-327.

[40] Pierantoni GM, Conte A, Rinaldo C, et al. Hmga1 null mouse embryonic fibroblasts display downregulation of spindle assembly checkpoint gene expression associated to nuclear and karyotypic abnormalities. Cell Cycle. 2016; 15(6): 812-818.

[41] Liu MJ, Zhao Y, Li QT, et al. HMGA1 promotes the progression of esophageal squamous cell carcinoma by elevating TKT-mediated upregulation of pentose phosphate pathway. Cell Death Dis. 2024; 15(7): 541.

[42] Yang JY, Lei XY, He KY, et al. HMGA1 drives chemoresistance in esophageal squamous cell carcinoma by suppressing ferroptosis. Cell Death Dis. 2024; 15(2): 158.

[43] Luo YX, Chen SK, Wang PD, et al. Genome-wide analysis of the RAV gene family in wheat and functional identification of TaRAV1 in salt stress. Int J Mol Sci. 2022; 23(16).

[44] Kovalchuk SI, Jensen ON, Rogowska-Wrzesinska A. FlashPack: fast and simple preparation of ultrahigh-performance capillary columns for LC-MS. Mol Cell Proteomic. 2019; 18(2): 383-390.

[45] Ding L, Chen X, Xu X, et al. PARP1 suppresses the transcription of PD-L1 by poly(ADP-Ribosyl)ating STAT3. Cancer Immunol Res. 2019; 7(1): 136-149.

[46] Zhang L, Li DQ. MORC2 regulates DNA damage response through a PARP1-dependent pathway. Nucleic Acids Res. 2019; 47(16): 8502-8520.

[47] Fang Z, Gong C, Yu S, et al. NFYB-induced high expression of E2F1 contributes to oxaliplatin resistance in colorectal cancer via the enhancement of CHK1 signaling. Cancer Lett. 2018; 415: 58-72.

[48] Pan X, Wang J, Guo L, et al. Identifying a confused cell identity for esophageal squamous cell carcinoma. Signal Transduct Target Ther. 2022; 7(1): 122.

[49] Zhang X, Peng L, Luo Y, et al. Dissecting esophageal squamous-cell carcinoma ecosystem by single-cell transcriptomic analysis. Nat Commun. 2021; 12(1): 5291.

[50] Ray Chaudhuri A, Nussenzweig A. The multifaceted roles of PARP1 in DNA repair and chromatin remodelling. Nat Rev Mol Cell Biol. 2017; 18(10): 610-621.

[51] Chen GZ, Zhu HC, Dai WS, Zeng XN, Luo JH, Sun XC. The mechanisms of radioresistance in esophageal squamous cell carcinoma and current strategies in radiosensitivity. J Thorac Dis. 2017; 9(3): 849-859.

[52] Morgan E, Soerjomataram I, Rumgay H, et al. The global landscape of esophageal squamous cell carcinoma and esophageal adenocarcinoma incidence and mortality in 2020 and projections to 2040: new estimates from GLOBOCAN 2020. Gastroenterology. 2022; 163(3): 649-658. e642.

[53] Zhang R, Lau LHS, Wu PIC, Yip HC, Wong SH. Endoscopic diagnosis and treatment of esophageal squamous cell carcinoma. Methods Mol Biol. 2020; 2129: 47-62.

[54] Kozlov SV, Waardenberg AJ, Engholm-Keller K, Arthur JW, Graham ME, Lavin M. Reactive oxygen species (ROS)-activated ATM-dependent phosphorylation of cytoplasmic substrates identified by large-scale phosphoproteomics screen. Mol Cell Proteomic. 2016; 15(3): 1032-1047.

[55] Song J, Cui D, Wang J, et al. Overexpression of HMGA1 confers radioresistance by transactivating RAD51 in cholangiocarcinoma. Cell Death Discover. 2021; 7(1): 322.

[56] Dantuma NP, van Attikum H. Spatiotemporal regulation of posttranslational modifications in the DNA damage response. EMBO J. 2016; 35(1): 6-23.

[57] Jungmichel S, Rosenthal F, Altmeyer M, Lukas J, Hottiger MO, Nielsen ML. Proteome-wide identification of poly(ADP-Ribosyl)ation targets in different genotoxic stress responses. Mol Cell. 2013; 52(2): 272-285.

[58] Ruscetti T, Lehnert BE, Halbrook J, et al. Stimulation of the DNA-dependent protein kinase by poly(ADP-ribose) polymerase. J Biol Chem. 1998; 273(23): 14461-14467.

[59] Hu Y, Petit SA, Ficarro SB, et al. PARP1-driven poly-ADP-ribosylation regulates BRCA1 function in homologous recombination-mediated DNA repair. Cancer Discov. 2014; 4(12): 1430-1447.

[60] Lebeaupin T, Smith R, Huet S, Timinszky G. Poly(ADP-Ribose)-dependent chromatin remodeling in DNA repair. Methods Mol Biol. 2017; 1608: 165-183.

[61] Ahel D, Horejsí Z, Wiechens N, et al. Poly(ADP-ribose)-dependent regulation of DNA repair by the chromatin remodeling enzyme ALC1. Science. 2009; 325(5945): 1240-1243.

[62] Alagoz M, Katsuki Y, Ogiwara H, et al. SETDB1, HP1 and SUV39 promote repositioning of 53BP1 to extend resection during homologous recombination in G2 cells. Nucleic Acids Res. 2015; 43(16): 7931-7944.

[63] Fitieh A, Locke AJ, Motamedi M, Ismail IH. The role of polycomb group protein BMI1 in DNA repair and genomic stability. Int J Mol Sci. 2021; 22(6).

[64] Chen B, Ge T, Jian M, et al. Transmembrane nuclease NUMEN/ENDOD1 regulates DNA repair pathway choice at the nuclear periphery. Nat Cell Biol. 2023; 25(7): 1004-1016.

[65] Abini-Agbomson S, Gretarsson K, Shih RM, et al. Catalytic and non-catalytic mechanisms of histone H4 lysine 20 methyltransferase SUV420H1. Mol Cell. 2023; 83(16): 2872-2883. e2877.

[66] Smith R, Zentout S, Rother M, et al. HPF1-dependent histone ADP-ribosylation triggers chromatin relaxation to promote the recruitment of repair factors at sites of DNA damage. Nat Struct Mol Biol. 2023; 30(5): 678-691.

[67] Slade D. PARP and PARG inhibitors in cancer treatment. Genes Dev. 2020; 34(5-6): 360-394.

[68] Bhamidipati D, Haro-Silerio JI, Yap TA, Ngoi N. PARP inhibitors: enhancing efficacy through rational combinations. Br J Cancer. 2023; 129(6): 904-916.

[69] Pujade-Lauraine E, Selle F, Scambia G, et al. Maintenance olaparib rechallenge in patients with platinum-sensitive relapsed ovarian cancer previously treated with a PARP inhibitor (OReO/ENGOT-ov38): a phase IIIb trial. Annal Oncol. 2023; 34(12): 1152-1164.

[70] Mateo J, Lord CJ, Serra V, et al. A decade of clinical development of PARP inhibitors in perspective. Annal Oncol. 2019; 30(9): 1437-1447.

[71] Gralewska P, Gajek A, Marczak A, et al. PARP inhibition increases the reliance on ATR/CHK1 checkpoint signaling leading to synthetic lethality-an alternative treatment strategy for epithelial ovarian cancer cells independent from HR effectiveness. Int J Mol Sci. 2020; 21(24).

[72] Serra V, Wang AT, Castroviejo-Bermejo M, et al. Identification of a molecularly-defined subset of breast and ovarian cancer models that respond to WEE1 or ATR inhibition, overcoming PARP inhibitor resistance. Clin Cancer Res. 2022; 28(20): 4536-4550.

[73] Pommier Y, O’Connor MJ, de Bono J. Laying a trap to kill cancer cells: PARP inhibitors and their mechanisms of action. Sci Transl Med. 2016; 8(362): 362ps317.

[74] Colicchia V, Petroni M, Guarguaglini G, et al. PARP inhibitors enhance replication stress and cause mitotic catastrophe in MYCN-dependent neuroblastoma. Oncogene. 2017; 36(33): 4682-4691.

[75] Parsels LA, Karnak D, Parsels JD, et al. PARP1 Trapping and DNA replication stress enhance radiosensitization with combined WEE1 and PARP inhibitors. Mol Cancer Res. 2018; 16(2): 222-232.

[76] Forment JV, O’Connor MJ. Targeting the replication stress response in cancer. Pharmacol Ther. 2018; 188: 155-167.

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