SRT1720 inhibits the growth of bladder cancer in organoids and murine models through the SIRT1-HIF axis
- 1 September 2021
- journal article
- research article
- Published by Springer Science and Business Media LLC in Oncogene
- Vol. 40 (42), 6081-6092
- https://doi.org/10.1038/s41388-021-01999-9
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.Keywords
This publication has 52 references indexed in Scilit:
- Radiosensitisation of bladder cancer cells by panobinostat is modulated by Ku80 expressionRadiotherapy and Oncology, 2013
- The Cancer Genome Atlas Pan-Cancer analysis projectNature Genetics, 2013
- Inhibition of SIRT1 Impairs the Accumulation and Transcriptional Activity of HIF-1α Protein under Hypoxic ConditionsPLOS ONE, 2012
- Redefining the relevance of established cancer cell lines to the study of mechanisms of clinical anti-cancer drug resistanceProceedings of the National Academy of Sciences of the United States of America, 2011
- Hypoxia Increases Sirtuin 1 Expression in a Hypoxia-inducible Factor-dependent MannerOnline Journal of Public Health Informatics, 2011
- Hypoxia-Inducible Factors and the Response to Hypoxic StressMolecular Cell, 2010
- Sirtuin 1 Modulates Cellular Responses to Hypoxia by Deacetylating Hypoxia-Inducible Factor 1αMolecular Cell, 2010
- Sirtuin 1 Reduction Parallels the Accumulation of Tau in Alzheimer DiseaseJournal of Neuropathology and Experimental Neurology, 2009
- Small molecule activators of SIRT1 as therapeutics for the treatment of type 2 diabetesNature, 2007
- Sirtuins: critical regulators at the crossroads between cancer and agingOncogene, 2007