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Targeting histone modifiers in bladder cancer therapy — preclinical and clinical evidence

Nature Reviews Urology (2024)Cite this article

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Abstract

Bladder cancer in the most advanced, muscle-invasive stage is lethal, and very limited therapeutic advances have been reported for decades. To date, cisplatin-based chemotherapy remains the first-line therapy for advanced bladder cancer. Late-line options have historically been limited. In the past few years, next-generation sequencing technology has enabled chromatin remodelling gene mutations to be characterized, showing that these alterations are more frequent in urothelial bladder carcinoma than in other cancer types. Histone modifiers have functional roles in tumour progression by modulating the expression of tumour suppressors and oncogenes and, therefore, have been considered as novel drug targets for cancer therapy. The roles of epigenetic reprogramming through histone modifications have been increasingly studied in bladder cancer, and the therapeutic efficacy of targeting those histone modifiers genetically or chemically is being assessed in preclinical studies. Results from preclinical studies in bladder cancer encouraged the investigation of some of these drugs in clinical trials, which yield mixed results. Further understanding of how alterations of histone modification mechanistically contribute to bladder cancer progression, drug resistance and tumour microenvironment remodelling will be required to facilitate clinical application of epigenetic drugs in bladder cancer.

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Fig. 1: Histone modifications potentially targetable in bladder cancer.

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Acknowledgements

This work was supported by the 1.3.5 project for disciplines of excellence, West China Hospital, Sichuan University ZYGD23001 and Sichuan Science and Technology Program (2023NSFSC1905).

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Authors and Affiliations

  1. Department of Urology, Institute of Urology, West China Hospital, Sichuan University, Chengdu, 610041, Sichuan, China

    Shiyu Zhang, Tianhai Lin, Xingyu Xiong, Ping Tan & Qiang Wei

  2. State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, Sichuan University, Chengdu, Sichuan, China

    Chong Chen & Ping Tan

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Contributions

S.Z. and X.X. researched data for the article. S.Z., T.L. and P.T. contributed substantially to discussion of the content. S.Z. wrote the article. Q.W., S.Z., C.C. and P.T. reviewed and/or edited the manuscript before submission.

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Zhang, S., Lin, T., Xiong, X. et al. Targeting histone modifiers in bladder cancer therapy — preclinical and clinical evidence. Nat Rev Urol (2024). https://doi.org/10.1038/s41585-024-00857-z

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