RNA mis-splicing drives viral mimicry response after DNMTi therapy in SETD2-mutant kidney cancer

被引：14

作者：

Li, Hong-Tao ^{[1
]}

Jang, H. Josh ^{[2
]}

Rohena-Rivera, Krizia ^{[3
]}

Liu, Minmin

Gujar, Hemant ^{[1
]}

Kulchycki, Justin ^{[2
]}

Zhao, Shuqing ^{[1
]}

Billet, Sandrin ^{[3
]}

Zhou, Xinyi ^{[1
]}

Weisenberger, Daniel J. ^{[4
]}

Gill, Inderbir

Jones, Peter A. ^{[2
]}

Bhowmick, Neil A. ^{[3
,5
]}

Liang, Gangning ^{[1
]}

机构：

[1] Univ Southern Calif Los Angeles, USC Norris Comprehens Canc Ctr, Dept Urol, Los Angeles, CA 90089 USA

[2] Andel Inst, Dept Epigenet, Grand Rapids, MI 49503 USA

[3] Cedars Sinai Med Ctr, Dept Biomed Sci, Los Angeles, CA 90048 USA

[4] Univ Southern Calif Los Angeles, USC Norris Comprehens Canc Ctr, Dept Biochem & Mol Med, Los Angeles, CA 90089 USA

[5] VA Greater Angeles Healthcare Syst, Los Angeles, CA 90073 USA

来源：

CELL REPORTS | 2023年 / 42卷 / 01期

基金：

美国国家卫生研究院;

关键词：

DNA METHYLATION; SETD2; EPIGENOME; EXPRESSION; CHROMATIN; TRIMETHYLATION; INTEGRATION; MUTATIONS; PATTERNS; TARGET;

D O I：

10.1016/j.celrep.2023.112016

中图分类号：

Q2 [细胞生物学];

学科分类号：

071009 ; 090102 ;

摘要：

Tumors with mutations in chromatin regulators present attractive targets for DNA hypomethylating agent 5-aza-20-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 immuno-therapy approaches.

引用

页数：22