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RNA mis-splicing drives viral mimicry response after DNMTi therapy in SETD2-mutant kidney cancer.
Li, Hong-Tao; Jang, H Josh; Rohena-Rivera, Krizia; Liu, Minmin; Gujar, Hemant; Kulchycki, Justin; Zhao, Shuqing; Billet, Sandrin; Zhou, Xinyi; Weisenberger, Daniel J; Gill, Inderbir; Jones, Peter A; Bhowmick, Neil A; Liang, Gangning.
Afiliação
  • Li HT; Department of Urology, USC Norris Comprehensive Cancer Center, University of Southern California, Los Angeles, CA 90089, USA.
  • Jang HJ; Department of Epigenetics, Van Andel Institute, Grand Rapids, MI 49503, USA.
  • Rohena-Rivera K; Department of Biomedical Sciences, Cedars-Sinai Medical Center, Los Angeles, CA 90048, USA.
  • Liu M; Department of Epigenetics, Van Andel Institute, Grand Rapids, MI 49503, USA.
  • Gujar H; Department of Urology, USC Norris Comprehensive Cancer Center, University of Southern California, Los Angeles, CA 90089, USA.
  • Kulchycki J; Department of Epigenetics, Van Andel Institute, Grand Rapids, MI 49503, USA.
  • Zhao S; Department of Urology, USC Norris Comprehensive Cancer Center, University of Southern California, Los Angeles, CA 90089, USA.
  • Billet S; Department of Biomedical Sciences, Cedars-Sinai Medical Center, Los Angeles, CA 90048, USA.
  • Zhou X; Department of Urology, USC Norris Comprehensive Cancer Center, University of Southern California, Los Angeles, CA 90089, USA.
  • Weisenberger DJ; Department of Biochemistry and Molecular Medicine, USC Norris Comprehensive Cancer Center, University of Southern California, Los Angeles, CA 90089, USA.
  • Gill I; Department of Urology, USC Norris Comprehensive Cancer Center, University of Southern California, Los Angeles, CA 90089, USA.
  • Jones PA; Department of Epigenetics, Van Andel Institute, Grand Rapids, MI 49503, USA. Electronic address: peter.jones@vai.org.
  • Bhowmick NA; Department of Biomedical Sciences, Cedars-Sinai Medical Center, Los Angeles, CA 90048, USA; VA Greater Los Angeles Healthcare System, Los Angeles, CA 90073, USA. Electronic address: neil.bhowmick@cshs.org.
  • Liang G; Department of Urology, USC Norris Comprehensive Cancer Center, University of Southern California, Los Angeles, CA 90089, USA. Electronic address: gliang@usc.edu.
Cell Rep ; 42(1): 112016, 2023 01 31.
Article em En | MEDLINE | ID: mdl-36662621
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.
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Texto completo: 1 Coleções: 01-internacional Base de dados: MEDLINE Assunto principal: Carcinoma de Células Renais / Neoplasias Renais Limite: Humans Idioma: En Revista: Cell Rep Ano de publicação: 2023 Tipo de documento: Article País de afiliação: Estados Unidos

Texto completo: 1 Coleções: 01-internacional Base de dados: MEDLINE Assunto principal: Carcinoma de Células Renais / Neoplasias Renais Limite: Humans Idioma: En Revista: Cell Rep Ano de publicação: 2023 Tipo de documento: Article País de afiliação: Estados Unidos