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Glycogen stores mediated by the p53-GYS1 feedback circuit engenders platinum resistance in ovarian clear cell carcinoma

Cell Death & Differentiation (2025)Cite this article

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Abstract

Ovarian cancer (OC) is a highly fatal and refractory malignancy affecting women, and platinum resistance remains a major clinical dilemma. Compared with other OC subtypes, ovarian clear cell carcinoma (OCCC) frequently exhibits increased platinum refractoriness, accompanied by increased glycogen levels, which promotes clear-cell morphology, and wild-type p53. However, the roles of these factors in platinum resistance of OCCC are unclear. Here, we investigated whether glycogen promotes OCCC resistance to platinum agents and reported that GYS1, a rate-limiting enzyme in glycogen synthesis, is clinically associated with poor prognosis and chemoresistance in OCCC. Mechanistically, p53 promotes GYS1 breakdown via the upregulation of RNF144a, whereas GYS1 induces the reversal of p53 ubiquitination and degradation by competitively binding to USP14, forming a positive feedback circuit. Under platinum stress, the accumulated glycogen is mobilized by the p53/GYS1 feedback circuit, which fuels energetic NADPH production, resulting in resistance to disulfidptosis and increased platinum resistance in OCCC. Collectively, our findings identify glycogen as a contributor to OCCC platinum resistance and elucidate the underlying mechanisms, highlighting a crucial p53/GYS1 positive feedback loop.

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Fig. 1: p53 regulated glycogen metabolism via GYS1.
Fig. 2: p53 abrogated GYS1 to eliminate glycogen by inducing RNF144a.
Fig. 3: GYS1 directly interacts with p53 and promotes its ubiquitination degradation.
Fig. 4: GYS1 competitively bound to USP14. leading to p53 degradation.
Fig. 5: P53 boosted the glycogen mobilization to fuel glycolysis and PPP pathway by blocking GYS1.
Fig. 6: The platinum resistance was driven by p53-GYS1 circuit.
Fig. 7: The expression and prognostic value of GYS1 in OCCC.

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Data availability

The LC-MS/MS data related to the interactive proteomics of p53 and GYS1 have been submitted to the PRIDE repository, under the accession number PXD057846 and PXD057878. Additionally, the RNA-seq data for TOV21G cells, both with and without GYS1 silencing, are available in the GEO database, with the accession code GSE281988. The authenticity of this research has been validated by uploading the key raw data onto the Research Data Deposit public platform (www.researchdata.org.cn) and the RDD number is RDDB2025404301.

References

  1. Lheureux S, Braunstein M, Oza AM. Epithelial ovarian cancer: Evolution of management in the era of precision medicine. CA Cancer J Clin. 2019;69:280–304.

    Article  PubMed  Google Scholar 

  2. Konstantinopoulos PA, Matulonis UA. Clinical and translational advances in ovarian cancer therapy. Nat Cancer. 2023;4:1239–57.

    Article  PubMed  Google Scholar 

  3. Kennedy AW, Markman M, Biscotti CV, Emery JD, Rybicki LA. Survival probability in ovarian clear cell adenocarcinoma. Gynecol Oncol. 1999;74:108–14.

    Article  PubMed  CAS  Google Scholar 

  4. Gong TT, Guo S, Liu FH, Huo YL, Zhang M, Yan S, et al. Proteomic characterization of epithelial ovarian cancer delineates molecular signatures and therapeutic targets in distinct histological subtypes. Nat Commun. 2023;14:7802.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  5. Oster M, Galhuber M, Krstic J, Steinhoff JS, Lenihan-Geels G, Wulff S, et al. Hepatic p53 is regulated by transcription factor FOXO1 and acutely controls glycogen homeostasis. J Biol Chem. 2022;298:102287.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  6. Shen J, Sun Y, Shen S, Luo X, Chen J, Zhu L. Pressure suppresses hepatocellular glycogen synthesis through activating the p53/Pten pathway. Mol Med Rep. 2019;19:5105–14.

    PubMed  PubMed Central  CAS  Google Scholar 

  7. Chen SL, Zhang CZ, Liu LL, Lu SX, Pan YH, Wang CH, et al. A GYS2/p53 Negative Feedback Loop Restricts Tumor Growth in HBV-Related Hepatocellular Carcinoma. Cancer Res. 2019;79:534–45.

    Article  PubMed  CAS  Google Scholar 

  8. Dauer P, Lengyel E. New Roles for Glycogen in Tumor Progression. Trends Cancer. 2019;5:396–9.

    Article  PubMed  CAS  Google Scholar 

  9. Stewart J, Cunningham N, Banerjee S. New therapies for clear cell ovarian carcinoma. Int J Gynecol Cancer. 2023;33:385–93.

    Article  PubMed  Google Scholar 

  10. Khan T, He Y, Kryza T, Harrington BS, Gunter JH, Sullivan MA, et al. Disruption of Glycogen Utilization Markedly Improves the Efficacy of Carboplatin against Preclinical Models of Clear Cell Ovarian Carcinoma. Cancers. 2020;12:869.

  11. Falantes JF, Trujillo P, Piruat JI, Calderon C, Marquez-Malaver FJ, Martin-Antonio B, et al. Overexpression of GYS1, MIF, and MYC is associated with adverse outcome and poor response to azacitidine in myelodysplastic syndromes and acute myeloid leukemia. Clin Lymphoma Myeloma Leuk. 2015;15:236–44.

    Article  PubMed  Google Scholar 

  12. de Heer EC, Zois CE, Bridges E, van der Vegt B, Sheldon H, Veldman WA, et al. Glycogen synthase 1 targeting reveals a metabolic vulnerability in triple-negative breast cancer. J Exp Clin Cancer Res. 2023;42:143.

    Article  PubMed  PubMed Central  Google Scholar 

  13. Chen SL, Huang QS, Huang YH, Yang X, Yang MM, He YF, et al. GYS1 induces glycogen accumulation and promotes tumor progression via the NF-kappaB pathway in Clear Cell Renal Carcinoma. Theranostics. 2020;10:9186–99.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  14. Liu X, Nie L, Zhang Y, Yan Y, Wang C, Colic M, et al. Actin cytoskeleton vulnerability to disulfide stress mediates disulfidptosis. Nat Cell Biol. 2023;25:404–14.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  15. Bragado P, Armesilla A, Silva A, Porras A. Apoptosis by cisplatin requires p53 mediated p38alpha MAPK activation through ROS generation. Apoptosis. 2007;12:1733–42.

    Article  PubMed  CAS  Google Scholar 

  16. Zhou P, Xia D, Wang Y, Lv H, Wang Z, Xing M, et al. Matrine derivate MASM protects murine MC3T3-E1 osteoblastic cells against dexamethasone-induced apoptosis via the regulation of USP14/p53. Artif Cells Nanomed Biotechnol. 2019;47:3720–8.

    Article  PubMed  CAS  Google Scholar 

  17. Ma YS, Wang XF, Yu F, Wu TM, Liu JB, Zhang YJ, et al. Inhibition of USP14 and UCH37 deubiquitinating activity by b-AP15 as a potential therapy for tumors with p53 deficiency. Sig Transduct Target Ther. 2020;5:30.

    Article  Google Scholar 

  18. Shulman RG, Rothman DL. The Glycogen Shunt Maintains Glycolytic Homeostasis and the Warburg Effect in Cancer. Trends Cancer. 2017;3:761–7.

    Article  PubMed  CAS  Google Scholar 

  19. Finley LWS. What is cancer metabolism? Cell. 2023;186:1670–88.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  20. Stine ZE, Schug ZT, Salvino JM, Dang CV. Targeting cancer metabolism in the era of precision oncology. Nat Rev Drug Discov. 2022;21:141–62.

    Article  PubMed  CAS  Google Scholar 

  21. Sun T, Liu Z, Yang Q. The role of ubiquitination and deubiquitination in cancer metabolism. Mol Cancer. 2020;19:146.

    Article  PubMed  PubMed Central  Google Scholar 

  22. Zois CE, Harris AL. Glycogen metabolism has a key role in the cancer microenvironment and provides new targets for cancer therapy. J Mol Med. 2016;94:137–54.

    Article  PubMed  CAS  Google Scholar 

  23. Tan DS, Miller RE, Kaye SB. New perspectives on molecular targeted therapy in ovarian clear cell carcinoma. Br J Cancer. 2013;108:1553–9.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  24. Liu Q, Li J, Zhang W, Xiao C, Zhang S, Nian C, et al. Glycogen accumulation and phase separation drives liver tumor initiation. Cell. 2021;184:5559–76 e5519.

    Article  PubMed  CAS  Google Scholar 

  25. Curtis M, Kenny HA, Ashcroft B, Mukherjee A, Johnson A, Zhang Y, et al. Fibroblasts Mobilize Tumor Cell Glycogen to Promote Proliferation and Metastasis. Cell Metab. 2019;29:141–55 e149.

    Article  PubMed  CAS  Google Scholar 

  26. Favaro E, Bensaad K, Chong MG, Tennant DA, Ferguson DJ, Snell C, et al. Glucose utilization via glycogen phosphorylase sustains proliferation and prevents premature senescence in cancer cells. Cell Metab. 2012;16:751–64.

    Article  PubMed  CAS  Google Scholar 

  27. Paek AL, Liu JC, Loewer A, Forrester WC, Lahav G. Cell-to-Cell Variation in p53 Dynamics Leads to Fractional Killing. Cell. 2016;165:631–42.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  28. Chen TY, Huang BM, Tang TK, Chao YY, Xiao XY, Lee PR, et al. Genotoxic stress-activated DNA-PK-p53 cascade and autophagy cooperatively induce ciliogenesis to maintain the DNA damage response. Cell Death Differ. 2021;28:1865–79.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  29. Yang Y, Yuan H, Zhao L, Guo S, Hu S, Tian M, et al. Targeting the miR-34a/LRPPRC/MDR1 axis collapse the chemoresistance in P53 inactive colorectal cancer. Cell Death Differ. 2022;29:2177–89.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  30. Thakur B, Ray P. p53 Loses grip on PIK3CA expression leading to enhanced cell survival during platinum resistance. Mol Oncol. 2016;10:1283–95.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  31. Hassin O, Oren M. Drugging p53 in cancer: one protein, many targets. Nat Rev Drug Discov. 2023;22:127–44.

    Article  PubMed  CAS  Google Scholar 

  32. Zhu H, Gao H, Ji Y, Zhou Q, Du Z, Tian L, et al. Targeting p53-MDM2 interaction by small-molecule inhibitors: learning from MDM2 inhibitors in clinical trials. J Hematol Oncol. 2022;15:91.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  33. Haupt Y, Maya R, Kazaz A, Oren M. Mdm2 promotes the rapid degradation of p53. Nature. 1997;387:296–9.

    Article  PubMed  CAS  Google Scholar 

  34. Foulkes WD, Stamp GW, Afzal S, Lalani N, McFarlane CP, Trowsdale J, et al. MDM2 overexpression is rare in ovarian carcinoma irrespective of TP53 mutation status. Br J Cancer. 1995;72:883–8.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  35. Jiang P, Du W, Mancuso A, Wellen KE, Yang X. Reciprocal regulation of p53 and malic enzymes modulates metabolism and senescence. Nature. 2013;493:689–93.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  36. Liang J, Li G, Liao J, Huang Z, Wen J, Wang Y, et al. Non-coding small nucleolar RNA SNORD17 promotes the progression of hepatocellular carcinoma through a positive feedback loop upon p53 inactivation. Cell Death Differ. 2022;29:988–1003.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  37. Donohue KJ, Fitzsimmons B, Bruntz RC, Markussen KH, Young LEA, Clarke HA, et al. Gys1 Antisense Therapy Prevents Disease-Driving Aggregates and Epileptiform Discharges in a Lafora Disease Mouse Model. Neurotherapeutics. 2023;20:1808–19.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  38. Kobel M, Reuss A, du, Bois A, Kommoss S, Kommoss F, et al. The biological and clinical value of p53 expression in pelvic high-grade serous carcinomas. J Pathol. 2010;222:191–8.

    Article  PubMed  CAS  Google Scholar 

Download references

Acknowledgements

This work was supported by grants from The National Natural Science Foundation of China (No. 82072853; No.82103220) and the Cancer Innovative Research Program of Sun Yat-sen University Cancer Center (CIRP-SYSUCC-0042).

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Author notes

  1. These authors contributed equally: Hao-Yu Liang, Rong-Zhen Luo, Ru Deng, Shi-Lu Chen.

Authors and Affiliations

  1. State Key Laboratory of Oncology in South China, Guangdong Provincial Clinical Research Center for Cancer, Sun Yat-sen University Cancer Center, Guangzhou, 510060, P. R. China

    Hao-Yu Liang, Rong-Zhen Luo, Ru Deng, Shi-Lu Chen, Xuan Liu, Xia Yang, Li-Jun Wei, Zong-Qiang Wei, Li-Yan Wu, Jing-Ping Yun & Li-Li Liu

  2. Department of Pathology, Sun Yat-sen University Cancer Center, Guangzhou, 510060, P. R. China

    Hao-Yu Liang, Rong-Zhen Luo, Ru Deng, Shi-Lu Chen, Xuan Liu, Xia Yang, Li-Jun Wei, Zong-Qiang Wei, Li-Yan Wu, Jing-Ping Yun & Li-Li Liu

  3. Department of Obstetrics and Gynecology, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou, 510080, P. R. China

    Hui-Min Shen

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Contributions

Conception and design: H-Y Liang, J-P Yun, L-L Liu. Development of methodology: H-Y Liang, X Yang. Acquisition of data (provided animals, acquired and managed patients, provided facilities, etc.): H-Y Liang, R-Z Luo, S-L Chen, R Deng, X Liu, L-J Wei, Z-Q Wei, LY Wu. Analysis and interpretation of data (e.g., statistical analysis, biostatistics, computational analysis): H-Y Liang, R-Z Luo, H-M Shen, J-P Yun, L-L Liu. Writing, review, and/or revision of the manuscript: H-Y Liang, R-Z Luo, L-L Liu. Administrative, technical, or material support e.g., reporting or organizing data, constructing databases): H-Y Liang, S-L Chen, R Deng. Study supervision: J-P Yun, L-L Liu.

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Correspondence to Hui-Min Shen, Jing-Ping Yun or Li-Li Liu.

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Liang, HY., Luo, RZ., Deng, R. et al. Glycogen stores mediated by the p53-GYS1 feedback circuit engenders platinum resistance in ovarian clear cell carcinoma. Cell Death Differ (2025). https://doi.org/10.1038/s41418-025-01500-z

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