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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...
Autores principales: | , , , , , , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
2023
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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 |
Sumario: | 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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