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SRT1720 inhibits the growth of bladder cancer in organoids and murine models through the SIRT1-HIF axis

Oncogene volume 40, pages 6081–6092 (2021)Cite this article

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Abstract

There are unmet clinical needs for novel therapeutic targets and drugs for bladder cancer. Majority of previous work relied on limited bladder cancer cell lines, which could not well represent the tumor heterogeneity and pathology of this disease. Recently, it has been shown that cancer organoids can recapitulate pathological and molecular properties of bladder cancer. Here, we report, by our knowledge, the first bladder cancer organoid-based small molecule screening for epigenetic drugs. We found that SRT1720, a Sirtuin 1 (SIRT1) activator, significantly inhibits the growth of both mouse and human bladder cancer organoids. And it also restrains the development of mouse in situ bladder cancer and human PDX bladder cancer. Mutation of Sirt1 promotes the growth of cancer organoids and decreases their sensitivity to SRT1720, which validate Sirt1 as the target of SRT1720 in bladder cancer. Mechanistically, SRT1720 treatment represses the hypoxia pathway through deacetylating HIF1α by activating Sirt1. Genetic or pharmaceutic inhibitions of HIF mimic the anti-tumor effect of SRT1720. Furthermore, the SIRT1-repressed gene signature is associated with the hypoxia target gene signature and poor prognosis in human bladder cancers. Thus, our study demonstrates the power of cancer organoid-based drug discovery and, in principle, identifies SRT1720 as a new treatment for bladder cancer.

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Fig. 1: Organoid-based epigenetics drug library screening identified SRT1720 as a candidate drug for bladder cancer.
Fig. 2: SRT1720 inhibited the growth of mouse bladder cancer organoids in vitro and organoids-derived orthotopic cancer in vivo.
Fig. 3: Validating SIRT1 as the target of SRT1720 in bladder cancer.
Fig. 4: SRT1720 repressed the HIF pathway in bladder cancer.
Fig. 5: SRT1720 inhibited the growth of bladder cancer through downregulating the HIF pathway.
Fig. 6: SRT1720 inhibited the growth of bladder cancer in patient-derived organoids and xenografts.
Fig. 7: SRT1720 downregulated the hypoxia pathway through activating SIRT1 to inhibit the growth of human bladder cancer.

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Data availability

All bulk RNA data generated by this study have been deposited in the GEO data sets (https://www.ncbi.nlm.nih.gov/gds). The data can be accessed under the accession number GSE155525. The code is available from the authors on request.

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Acknowledgements

We thank all Chen-Liu laboratory members for their invaluable suggestions and technical support, and Wei team members for patient counseling.

Funding

This work was supported by the National Key R&D Program of China (Grant No. 2017YFA0505600), National Natural Science Foundation of China (Grant No. 82002692), 1.3.5. Project for Disciplines of Excellence, West China Hospital, Sichuan University (Grant No. ZYGD18011 and ZY2016104), Post-Doctor Research Project of Sichuan University (Grant No. 2021SCU12016), and Post-Doctor Research Project, West China Hospital, Sichuan University (Grant No. 19HXBH057).

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  1. These authors contributed equally: Ping Tan, Manli Wang.

Authors and Affiliations

  1. Department of Urology, Institute of Urology, Department of Thoracic Oncology, State Key Laboratory of Biotherapy and Cancer Center, Huaxi MR Research Center (HMRRC), Department of Radiology, West China Hospital, Sichuan University, Chengdu, China

    Ping Tan, Manli Wang, Ailing Zhong, Yiyun Wang, Jiajia Du, Jian Wang, Lu Qi, Zhanying Bi, Peng Zhang, Tianhai Lin, Jiapeng Zhang, Lu Yang, Jingyao Chen, Ping Han, Qiyong Gong, Yu Liu, Chong Chen & Qiang Wei

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Contributions

PT, MW, YL, CC, and QW conceived the project, designed experiments, and wrote the paper. PT, MW, YW, JD, JW, LQ, ZB, JZ, and JC performed experiments and analyzed data. PZ, TL, PH, LY, and QG did patient counseling. AZ performed RNA-seq and bioinformatics analysis.

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Correspondence to Chong Chen or Qiang Wei.

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The authors declare no competing interests.

Ethics approval and consent to participate

The study was approved by the Ethical Research Committee of the West China Hospital (2019-933/2020-330). Written informed consent was obtained from all patients involved. All patients had a confirmed pathologic diagnosis of MIBC and underwent radical cystectomy.

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Tan, P., Wang, M., Zhong, A. et al. SRT1720 inhibits the growth of bladder cancer in organoids and murine models through the SIRT1-HIF axis. Oncogene 40, 6081–6092 (2021). https://doi.org/10.1038/s41388-021-01999-9

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