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

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.

 

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Overexpression of DOT1L in RCC is associated with poor clinical outcomes, and suppression of DOT1L using a chemical inhibitor (SGC0946) or genetic methods reduces the growth and invasion of renal cancer cells, resulting in S-phase arrest.

The study also suggests that DOT1L promotes the transcription of STAT5B, a signaling protein, via H3K79me2, a specific histone modification. CDK6, a downstream effector of STAT5B, mediates cell cycle arrest. Suppression of DOT1L reduces the expression of STAT5B and subsequently CDK6, leading to cell cycle arrest and inhibition of RCC proliferation and invasion.

These findings suggest that targeting DOT1L may be a promising therapeutic strategy for RCC. However, further research is needed to validate the effectiveness and safety of DOT1L inhibitors in preclinical and clinical settings.

Related Products

Cat.No. Product Name Information
S7079 SGC 0946 SGC 0946 is a highly potent and selective DOT1L methyltransferase inhibitor with IC50 of 0.3 nM in a cell-free assay, is inactive against a panel of 12 PMTs and DNMT1.

Related Targets

Histone Methyltransferase DOT1