biostudies-literatureLukinovic VINCaAmerican Cancer SocietyFondation ARCCareer Enhancement Grant—The University of Texas NIH SPORE in Lung CancerAndrew Sabin Family Foundation Scientist and CPRIT Scholar in Cancer ResearchANR JCJCNCI NIH HHSFondation pour la Recherche MédicaleProFINIHDeutsche Forschungsgemeinschaft FellowshipDOD PRCRP Career Development Award2158-2179https://www.ebi.ac.uk/biostudies/studies/S-EPMC9437563biostudies-literatureUnknown12(9)Small cell lung cancer (SCLC) is the most fatal form of lung cancer, with dismal survival, limited therapeutic options, and rapid development of chemoresistance. We identified the lysine methyltransferase SMYD3 as a major regulator of SCLC sensitivity to alkylation-based chemotherapy. RNF113A methylation by SMYD3 impairs its interaction with the phosphatase PP4, controlling its phosphorylation levels. This cross-talk between posttranslational modifications acts as a key switch in promoting and maintaining RNF113A E3 ligase activity, essential for its role in alkylation damage response. In turn, SMYD3 inhibition restores SCLC vulnerability to alkylating chemotherapy. Our study sheds light on a novel role of SMYD3 in cancer, uncovering this enzyme as a mediator of alkylation damage sensitiviCancer discoverySMYD3 Impedes Small Cell Lung Cancer Sensitivity to Alkylation Damage through RNF113A Methylation-Phosphorylation Cross-talk.PMC9437563PJA 20181207702ANR-10-INBS-08-01K99CA255936K99 CA255936ANR-16-CE11-0018R01CA236949R01CA236118RR160078CA181486P50CA070907R01 CA236118R01 CA272844R01 CA227001P50 CA070907PLBIO19-021SPF201809006930R01 CA236949RSG-18-156-01-DMCHA8434/1-1R01 CA193318P01 CA092584Roth GSJansen PWTCCoute YTsao NAhmad THausmann SRodell RReynoird NOyeniran CLukinovic VBrickner JRVermeulen MCasanova AGHainaut PTardif MMazur PKBenitez AMChuffart FMosammaparast NVayr JfalseSMYD3 Impedes Small Cell Lung Cancer Sensitivity to Alkylation Damage through RNF113A Methylation-Phosphorylation Cross-talk.Small cell lung cancer (SCLC) is the most fatal form of lung cancer, with dismal survival, limited therapeutic options, and rapid development of chemoresistance. We identified the lysine methyltransferase SMYD3 as a major regulator of SCLC sensitivity to alkylation-based chemotherapy. RNF113A methylation by SMYD3 impairs its interaction with the phosphatase PP4, controlling its phosphorylation levels. This cross-talk between posttranslational modifications acts as a key switch in promoting and maintaining RNF113A E3 ligase activity, essential for its role in alkylation damage response. In turn, SMYD3 inhibition restores SCLC vulnerability to alkylating chemotherapy. Our study sheds light on a novel role of SMYD3 in cancer, uncovering this enzyme as a mediator of alkylation damage sensitivi2022-01-01T00:00:00Z2022 Sep2026-05-27T22:31:11.163Z2025-02-19T02:37:58.71ZS-EPMC94375633581931910.1158/2159-8290.CD-21-0205