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

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...

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Autores principales: 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
Formato: Online Artículo Texto
Lenguaje:English
Publicado: 2023
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10034851/
https://www.ncbi.nlm.nih.gov/pubmed/36662621
http://dx.doi.org/10.1016/j.celrep.2023.112016
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author 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
author_facet 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
author_sort Li, Hong-Tao
collection PubMed
description 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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spelling pubmed-100348512023-03-23 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 Cell Rep Article 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. 2023-01-31 2023-01-19 /pmc/articles/PMC10034851/ /pubmed/36662621 http://dx.doi.org/10.1016/j.celrep.2023.112016 Text en https://creativecommons.org/licenses/by-nc-nd/4.0/This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/ (https://creativecommons.org/licenses/by-nc-nd/4.0/) ).
spellingShingle Article
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
RNA mis-splicing drives viral mimicry response after DNMTi therapy in SETD2-mutant kidney cancer
title RNA mis-splicing drives viral mimicry response after DNMTi therapy in SETD2-mutant kidney cancer
title_full RNA mis-splicing drives viral mimicry response after DNMTi therapy in SETD2-mutant kidney cancer
title_fullStr RNA mis-splicing drives viral mimicry response after DNMTi therapy in SETD2-mutant kidney cancer
title_full_unstemmed RNA mis-splicing drives viral mimicry response after DNMTi therapy in SETD2-mutant kidney cancer
title_short RNA mis-splicing drives viral mimicry response after DNMTi therapy in SETD2-mutant kidney cancer
title_sort rna mis-splicing drives viral mimicry response after dnmti therapy in setd2-mutant kidney cancer
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10034851/
https://www.ncbi.nlm.nih.gov/pubmed/36662621
http://dx.doi.org/10.1016/j.celrep.2023.112016
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