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.

根据各种临床试验，二甲双胍对前列腺癌 (PCa) 的治疗效果似乎不确定。二甲双胍治疗失败可能归因于高频率的转录失调，从而导致耐药性。然而，其根本机制仍不清楚。在这项研究中，我们发现证据表明 PCa 细胞中的二甲双胍耐药性可能与细胞周期重新激活有关。超级增强子（SE）是关键的调控元件，已被证明与多种癌症的耐药性相关。我们对二甲双胍耐药 (MetR) PCa 细胞中 SE 的分析揭示了与前列腺素还原酶 1 (PTGR1) 表达的相关性，通过单细胞转录组测序发现，在二甲双胍耐药的细胞群中，前列腺素还原酶 1 (PTGR1) 表达显着增加。我们的功能实验表明，PTGR1 过表达通过促进从 G0/G1 期进展到 S 和 G2/M 期来加速细胞周期进程，导致对二甲双胍的敏感性降低。此外，我们还确定了显着增加 PTGR1 表达的关键转录因子，例如 SRF 和 RUNX3，为解决 PCa 中的二甲双胍耐药性提供了潜在的新靶标。总之，我们的研究为二甲双胍耐药的细胞机制和 SE-TFs-PTGR1 轴的调节提供了新的线索，为增强二甲双胍治疗 PCa 的疗效提供了潜在途径。