DLGAP5 enhances bladder cancer chemoresistance by regulating glycolysis through MYC stabilization

Our study shows that DLGAP5 enhances gemcitabine resistance in bladder cancer by stabilizing MYC protein via USP11-mediated deubiquitination. This interaction boosts MYC-driven glycolysis, suggesting that targeting the DLGAP5-USP11-MYC axis could overcome resistance.
Published in Cancer and Genetics & Genomics
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Our lastest publication demonstrated that high DLGAP5 expression in bladder cancer correlates with poor clinical outcomes, and that increased DLGAP5 promotes bladder cancer development [1]. Building on that finding, the current study further reveals that DLGAP5 potentially affects BLCA cell chemosensitivity to gemcitabine, expanding and enriching the function of DLGAP5 in bladder cancer as well as the future application prospects of DLGAP5.

 The Warburg effect plays a pivotal role in fostering chemotherapy resistance in tumors [2]. It describes how cancer cells generate energy through glycolysis even in the presence of oxygen, resulting in increased lactate production [3, 4]. The Warburg effect enhances tumor characteristics linked to resistance to therapeutic agents, including increased drug efflux, improved DNA damage repair mechanisms, modifications in drug metabolism, epigenetic changes, mutations affecting drug targets, activation of survival pathways, and mechanisms that evade apoptosis and immune responses [5]. Therefore, unraveling the mechanisms underlying glycolytic changes during gemcitabine treatment for bladder cancer may provide insights into the development of chemotherapy resistance and offer strategies to overcome the carcinoma.

Here, we underscore the pivotal role of DLGAP5 in regulating glycolytic activity in BLCA and enhancing resistance to gemcitabine chemotherapy. Further validation studies revealed the interaction of DLGAP5 with MYC and its facilitation of MYC deubiquitination via USP11, thereby increasing glycolytic levels in BLCA cells. This reciprocal reinforcement among DLGAP5, USP11, and MYC substantially contributes to BLCA resistance.

Taken together, our research identifies DLGAP5 as a potential biomarker for predicting chemotherapy response and proposes targeting the DLGAP5/MYC/glycolysis metabolic pathway as a strategy to overcome gemcitabine resistance in bladder cancer.

References:
[1] Zhou F, Deng Z, Shen D, Lu M, Li M, Yu J, et al. DLGAP5 triggers proliferation and metastasis of bladder cancer by stabilizing E2F1 via USP11. Oncogene. 2024; 43: 594-607.
[2] Icard P, Shulman S, Farhat D, Steyaert J-M, Alifano M, Lincet H. How the Warburg effect supports aggressiveness and drug resistance of cancer cells? Drug Resist Updat. 2018; 38.
[3] Warburg O, Wind F, Negelein E. The metabolism of tumors in the body. J Gen Physiol. 1927; 8: 519-30.
[4] Warburg O. On the origin of cancer cells. Science. 1956; 123: 309-14.
[5] Holohan C, Van Schaeybroeck S, Longley DB, Johnston PG. Cancer drug resistance: an evolving paradigm. Nat Rev Cancer. 2013; 13: 714-26.

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