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

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....

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Autores principales: Ye, Jianheng, Cai, Shanghua, Feng, Yuanfa, Li, Jinchuang, Cai, Zhiduan, Deng, Yulin, Liu, Ren, Zhu, Xuejin, Lu, Jianming, Zhuo, Yangjia, Liang, Yingke, Xie, Jianjiang, Zhang, Yanqiong, He, Huichan, Han, Zhaodong, Jia, Zhenyu, Zhong, Weide
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Nature Publishing Group UK 2023
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10427640/
https://www.ncbi.nlm.nih.gov/pubmed/37582751
http://dx.doi.org/10.1038/s41392-023-01516-2
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author Ye, Jianheng
Cai, Shanghua
Feng, Yuanfa
Li, Jinchuang
Cai, Zhiduan
Deng, Yulin
Liu, Ren
Zhu, Xuejin
Lu, Jianming
Zhuo, Yangjia
Liang, Yingke
Xie, Jianjiang
Zhang, Yanqiong
He, Huichan
Han, Zhaodong
Jia, Zhenyu
Zhong, Weide
author_facet Ye, Jianheng
Cai, Shanghua
Feng, Yuanfa
Li, Jinchuang
Cai, Zhiduan
Deng, Yulin
Liu, Ren
Zhu, Xuejin
Lu, Jianming
Zhuo, Yangjia
Liang, Yingke
Xie, Jianjiang
Zhang, Yanqiong
He, Huichan
Han, Zhaodong
Jia, Zhenyu
Zhong, Weide
author_sort Ye, Jianheng
collection PubMed
description 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.
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spelling pubmed-104276402023-08-17 Metformin escape in prostate cancer by activating the PTGR1 transcriptional program through a novel super-enhancer Ye, Jianheng Cai, Shanghua Feng, Yuanfa Li, Jinchuang Cai, Zhiduan Deng, Yulin Liu, Ren Zhu, Xuejin Lu, Jianming Zhuo, Yangjia Liang, Yingke Xie, Jianjiang Zhang, Yanqiong He, Huichan Han, Zhaodong Jia, Zhenyu Zhong, Weide Signal Transduct Target Ther Article 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. Nature Publishing Group UK 2023-08-16 /pmc/articles/PMC10427640/ /pubmed/37582751 http://dx.doi.org/10.1038/s41392-023-01516-2 Text en © The Author(s) 2023 https://creativecommons.org/licenses/by/4.0/Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/ (https://creativecommons.org/licenses/by/4.0/) .
spellingShingle Article
Ye, Jianheng
Cai, Shanghua
Feng, Yuanfa
Li, Jinchuang
Cai, Zhiduan
Deng, Yulin
Liu, Ren
Zhu, Xuejin
Lu, Jianming
Zhuo, Yangjia
Liang, Yingke
Xie, Jianjiang
Zhang, Yanqiong
He, Huichan
Han, Zhaodong
Jia, Zhenyu
Zhong, Weide
Metformin escape in prostate cancer by activating the PTGR1 transcriptional program through a novel super-enhancer
title Metformin escape in prostate cancer by activating the PTGR1 transcriptional program through a novel super-enhancer
title_full Metformin escape in prostate cancer by activating the PTGR1 transcriptional program through a novel super-enhancer
title_fullStr Metformin escape in prostate cancer by activating the PTGR1 transcriptional program through a novel super-enhancer
title_full_unstemmed Metformin escape in prostate cancer by activating the PTGR1 transcriptional program through a novel super-enhancer
title_short Metformin escape in prostate cancer by activating the PTGR1 transcriptional program through a novel super-enhancer
title_sort metformin escape in prostate cancer by activating the ptgr1 transcriptional program through a novel super-enhancer
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10427640/
https://www.ncbi.nlm.nih.gov/pubmed/37582751
http://dx.doi.org/10.1038/s41392-023-01516-2
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