{"doi":"10.1016/j.celrep.2023.112016","title":"RNA mis-splicing drives viral mimicry response after DNMTi therapy in SETD2-mutant kidney cancer","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.","journal":"Cell Reports","year":2023,"id":331864,"datarank":0.0,"base_score":0.0,"endowment":0.0,"self_citation_contribution":0.0,"citation_network_contribution":0.0,"self_endowment_contribution":0.0,"citer_contribution":0.0,"corpus_percentile":null,"corpus_rank":null,"citation_count":26,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.959,"is_data_producer":false,"deposit_databanks":null,"is_oa":true,"file_count":0,"downloads":0,"has_version_chain":false,"published_date":"2023-01-01","fair_score":null,"fair_percentile":null,"algorithm_id":"datarank_citation_only_1hop_v6","ranking_scope":"data_only","authors":[{"id":280738,"name":"H. Josh Jang","orcid":"0000-0001-9654-4448","position":1,"is_corresponding":false},{"id":1057336,"name":"Krizia Rohena-Rivera","orcid":"0000-0003-3391-8742","position":2,"is_corresponding":false},{"id":1057337,"name":"Minmin Liu","orcid":"0000-0002-7405-8972","position":3,"is_corresponding":false},{"id":772912,"name":"Hemant Gujar","orcid":"0000-0001-5896-7562","position":4,"is_corresponding":false},{"id":1037176,"name":"Justin R. Kulchycki","orcid":"0000-0002-4000-9320","position":5,"is_corresponding":false},{"id":838061,"name":"Shuqing Zhao","orcid":"0000-0002-3072-3731","position":6,"is_corresponding":false},{"id":1057889,"name":"Sandrin Billet","orcid":null,"position":7,"is_corresponding":false},{"id":1057338,"name":"Xinyi Zhou","orcid":"0000-0003-2319-6301","position":8,"is_corresponding":false},{"id":1834,"name":"Daniel J. Weisenberger","orcid":"0000-0001-8303-2603","position":9,"is_corresponding":false},{"id":706052,"name":"Inderbir S. Gill","orcid":"0000-0002-5113-7846","position":10,"is_corresponding":false},{"id":619292,"name":"Peter A. Jones","orcid":"0000-0001-8309-4767","position":11,"is_corresponding":false},{"id":370842,"name":"Neil A. Bhowmick","orcid":"0000-0001-8747-5989","position":12,"is_corresponding":false},{"id":772917,"name":"Gangning Liang","orcid":"0000-0001-8664-922X","position":13,"is_corresponding":false},{"id":732272,"name":"Hongtao Li","orcid":"0000-0001-6366-0741","position":0,"is_corresponding":true}],"reference_count":87,"raw_metadata":null,"created_at":"2026-07-19T01:09:25.015646Z","pmid":"36662621","pmcid":null,"fwci":null,"citation_percentile":null,"influential_citations":0,"oa_status":null,"license":null,"views":0,"total_file_size_bytes":0,"version_count":0,"fair_f":null,"fair_a":null,"fair_i":null,"fair_r":null,"fair_zscore":null,"fair_rationale":null,"fair_model":null,"fair_agent_version":null,"fair_fulltext_source":null,"fair_has_llm":null,"fair_computed_at":null,"clinical_trials":[],"software_tools":[],"db_accessions":[],"linked_datasets":[],"topics":[]}