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Metformin escape in prostate cancer by activating the PTGR1 transcriptional program through a novel super-enhancer

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收录情况： ◇ 统计源期刊 ◇ CSCD-C ◇ 卓越：领军期刊

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机构： [1]Department of Urology, Guangzhou First People’s Hospital, South China University of Technology, 510180 Guangzhou, Guangdong, China [2]Urology Key Laboratory ofGuangdong Province, The First Affiliated Hospital of Guangzhou Medical University, Guangzhou Medical University, 510230 Guangzhou, Guangdong, China [3]GuangzhouNational Laboratory, No. 9 XingDaoHuanBei Road, Guangzhou International Bio Island, 510005 Guangzhou, Guangdong, China [4]Institute of Chinese Materia Medica, ChinaAcademy of Chinese Medical Sciences, 100700 Beijing, China [5]Department of Botany and Plant Sciences, University of California, Riverside, CA 92507, USA [6]Graduate Program inGenetics, Genomics & Bioinformatics, University of California, Riverside, CA 92507, USA [7]State Key Laboratory of Quality Research in Chinese Medicine, Macau University ofScience and Technology, Taipa, 999078 Macau, China

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The therapeutic efficacy of metformin in prostate cancer (PCa) appears uncertain based on various clinical trials. Metformin treatment failure may be attributed to the high frequency of transcriptional dysregulation, which leads to drug resistance. However, the underlying mechanism is still unclear. In this study, we found evidences that metformin resistance in PCa cells may be linked to cell cycle reactivation. Super-enhancers (SEs), crucial regulatory elements, have been shown to be associated with drug resistance in various cancers. Our analysis of SEs in metformin-resistant (MetR) PCa cells revealed a correlation with Prostaglandin Reductase 1 (PTGR1) expression, which was identified as significantly increased in a cluster of cells with metformin resistance through single-cell transcriptome sequencing. Our functional experiments showed that PTGR1 overexpression accelerated cell cycle progression by promoting progression from the G0/G1 to the S and G2/M phases, resulting in reduced sensitivity to metformin. Additionally, we identified key transcription factors that significantly increase PTGR1 expression, such as SRF and RUNX3, providing potential new targets to address metformin resistance in PCa. In conclusion, our study sheds new light on the cellular mechanism underlying metformin resistance and the regulation of the SE-TFs-PTGR1 axis, offering potential avenues to enhance metformin's therapeutic efficacy in PCa.© 2023. West China Hospital, Sichuan University.

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出版当年[2022]版：

大类 | 1 区

医学

小类 | 1 区生化与分子生物学 1 区细胞生物学

最新[2025]版：

大类 | 1 区

医学

小类 | 1 区生化与分子生物学 1 区细胞生物学

第一作者：

第一作者机构： [1]Department of Urology, Guangzhou First People’s Hospital, South China University of Technology, 510180 Guangzhou, Guangdong, China

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通讯作者：

通讯机构： [1]Department of Urology, Guangzhou First People’s Hospital, South China University of Technology, 510180 Guangzhou, Guangdong, China [2]Urology Key Laboratory ofGuangdong Province, The First Affiliated Hospital of Guangzhou Medical University, Guangzhou Medical University, 510230 Guangzhou, Guangdong, China [3]GuangzhouNational Laboratory, No. 9 XingDaoHuanBei Road, Guangzhou International Bio Island, 510005 Guangzhou, Guangdong, China [5]Department of Botany and Plant Sciences, University of California, Riverside, CA 92507, USA [6]Graduate Program inGenetics, Genomics & Bioinformatics, University of California, Riverside, CA 92507, USA [7]State Key Laboratory of Quality Research in Chinese Medicine, Macau University ofScience and Technology, Taipa, 999078 Macau, China

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