DOT1L promotes cell proliferation and invasion by epigenetically regulating STAT5B in renal cell carcinoma

Yanguang Hou; Shiyu Huang; Jiachen Liu; Lei Wang; Yan Yuan; Hao Liu; Xiaodong Weng; Zhiyuan Chen; Juncheng Hu; Xiuheng Liu

DOT1L promotes cell proliferation and invasion by epigenetically regulating STAT5B in renal cell carcinoma

Am J Cancer Res. 2023 Jan 15;13(1):276-292. eCollection 2023.

Authors

Yanguang Hou^{1

2}, Shiyu Huang^{1

2}, Jiachen Liu^{1

2}, Lei Wang¹, Yan Yuan¹, Hao Liu¹, Xiaodong Weng¹, Zhiyuan Chen¹, Juncheng Hu^{1

2}, Xiuheng Liu¹

Affiliations

¹ Department of Urology, Renmin Hospital of Wuhan University Wuhan 430060, Hubei, PR China.
² Wuhan University Institute of Urologic Disease, Renmin Hospital of Wuhan University Wuhan 430060, Hubei, PR China.

PMID: 36777512
PMCID: PMC9906067

Abstract

DOT1L, the only histone H3 lysine 79 methyltransferase, has a prominent effect on promoting the progression of various malignancies, yet the functional contribution of DOT1L to renal cell carcinoma (RCC) progression remains unclear. DOT1L is overexpressed in RCC and linked to poor clinical outcomes. Chemical (SGC0946) or genetic suppression of DOT1L attenuates the growth and invasion of renal cancer cells and results in S-phase arrest. STAT5B expression was suppressed after DOT1L knockdown, and STAT5B overexpression rescued the DOT1L silencing-induced decrease in cell proliferation. DOT1L was found to epigenetically promote the transcription of STAT5B via H3K79me2, and CDK6 acted as a downstream effector of STAT5B to mediate cell cycle arrest. Our study confirmed that DOT1L promotes STAT5B expression in a histone methyltransferase-dependent manner. Downregulation of DOT1L inhibited RCC proliferation and invasion. Thus, targeting DOT1L might be a potential therapeutic intervention for RCC.

Keywords: CDK6; DOT1L; Renal cell carcinoma; STAT5B; histone methylation.