Integrated high-throughput analysis identifies super enhancers in metastatic castration-resistant prostate cancer

Jie Zeng; Jiahong Chen; Maozhang Li; Chuanfan Zhong; Zezhen Liu; Yan Wang; Yuejiao Li; Funeng Jiang; Shumin Fang; Weide Zhong

doi:10.3389/fphar.2023.1191129

Integrated high-throughput analysis identifies super enhancers in metastatic castration-resistant prostate cancer

Front Pharmacol. 2023 May 24:14:1191129. doi: 10.3389/fphar.2023.1191129. eCollection 2023.

Authors

Affiliations

¹ Department of Urology, The Second Affiliated Hospital, School of Medicine, South China University of Technology, Guangzhou, Guangdong, China.
² Department of Urology, Huizhou Municipal Central Hospital, Huizhou, Guangdong, China.
³ Zhujiang Hospital, Southern Medical University, Guangzhou, Guangdong, China.
⁴ Department of Urology, Minimally Invasive Surgery Center, The First Affiliated Hospital of Guangzhou Medical University, and Guangdong Key Laboratory of Urology, Guangzhou, Guangdong, China.

Abstract

Background: Metastatic castration-resistant prostate cancer (mCRPC) is a highly aggressive stage of prostate cancer, and non-mutational epigenetic reprogramming plays a critical role in its progression. Super enhancers (SE), epigenetic elements, are involved in multiple tumor-promoting signaling pathways. However, the SE-mediated mechanism in mCRPC remains unclear. Methods: SE-associated genes and transcription factors were identified from a cell line (C4-2B) of mCRPC by the CUT&Tag assay. Differentially expressed genes (DEGs) between mCRPC and primary prostate cancer (PCa) samples in the GSE35988 dataset were identified. What's more, a recurrence risk prediction model was constructed based on the overlapping genes (termed SE-associated DEGs). To confirm the key SE-associated DEGs, BET inhibitor JQ1 was applied to cells to block SE-mediated transcription. Finally, single-cell analysis was performed to visualize cell subpopulations expressing the key SE-associated DEGs. Results: Nine human TFs, 867 SE-associated genes and 5417 DEGs were identified. 142 overlapping SE-associated DEGs showed excellent performance in recurrence prediction. Time-dependent receiver operating characteristic (ROC) curve analysis showed strong predictive power at 1 year (0.80), 3 years (0.85), and 5 years (0.88). The efficacy of his performance has also been validated in external datasets. In addition, FKBP5 activity was significantly inhibited by JQ1. Conclusion: We present a landscape of SE and their associated genes in mCPRC, and discuss the potential clinical implications of these findings in terms of their translation to the clinic.

Keywords: CUT&Tag; mCRPC; prostate cancer; super enhancer; transcription factor.

Grants and funding

This work was supported by grants from the National Natural Science Foundation of China (No.82072813), Natural Science Foundation of Guangdong Province, China (No. 2022A1515010344), Huizhou High Level Hospital Construction Science and Technology Special Project (No. 2022CZ010004), and Guangzhou Municipal Science and Technology Project (202102080029, 202201020386).