RNA mis-splicing drives viral mimicry response after DNMTi therapy in SETD2-mutant kidney cancer
Hongtao Li, H. Josh Jang, Krizia Rohena-Rivera, Minmin Liu, Hemant Gujar, Justin R. Kulchycki, Shuqing Zhao, Sandrin Billet, Xinyi Zhou, Daniel J. Weisenberger, Inderbir S. Gill, Peter A. Jones, Neil A. Bhowmick, Gangning Liang
Abstract
Tumors with mutations in chromatin regulators present attractive targets for DNA hypomethylating agent 5-aza-2'-deoxycytidine (DAC) therapy, which further disrupts cancer cells' epigenomic fidelity and reactivates transposable element (TE) expression to drive viral mimicry responses. SETD2 encodes a histone methyltransferase (H3K36me3) and is prevalently mutated in advanced kidney cancers. Here, we show that SETD2-mutant kidney cancer cells are especially sensitive in vitro and in vivo to DAC treatment. We find that the viral mimicry response are direct consequences of mis-splicing events, such as exon inclusions or extensions, triggered by DAC treatment in an SETD2-loss context. Comprehensive epigenomic analysis reveals H3K9me3 deposition, rather than DNA methylation dynamics, across intronic TEs might contribute to elevated mis-splicing rates. Through epigenomic and transcriptomic analyses, we show that SETD2-deficient kidney cancers are prone to mis-splicing, which can be therapeutically exacerbated with DAC treatment to increase viral mimicry activation and provide synergy with combinatorial immunotherapy approaches.