SMYD3 Impedes Small Cell Lung Cancer Sensitivity to Alkylation Damage through RNF113A Methylation–Phosphorylation Cross-talk
| Autor: | Valentina Lukinović, Simone Hausmann, Gael S. Roth, Clement Oyeniran, Tanveer Ahmad, Ning Tsao, Joshua R. Brickner, Alexandre G. Casanova, Florent Chuffart, Ana Morales Benitez, Jessica Vayr, Rebecca Rodell, Marianne Tardif, Pascal W.T.C. Jansen, Yohann Couté, Michiel Vermeulen, Pierre Hainaut, Pawel K. Mazur, Nima Mosammaparast, Nicolas Reynoird |
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| Přispěvatelé: | Institut de Recherche Interdisciplinaire de Grenoble (IRIG), Direction de Recherche Fondamentale (CEA) (DRF (CEA)), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA), ANR-16-CE11-0018,S3S,Signalisation physiologique et pathologique de la lysine méthyltransférase SMYD3(2016), Reynoird, Nicolas |
| Jazyk: | angličtina |
| Rok vydání: | 2022 |
| Předmět: |
MESH: Cell Nucleus
MESH: RNA Processing Post-Transcriptional Lung Neoplasms MESH: DNA Helicases MESH: AlkB Homolog 3 Alpha-Ketoglutarate-Dependent Dioxygenase [SDV.CAN]Life Sciences [q-bio]/Cancer Methylation [SDV.MHEP.PSR]Life Sciences [q-bio]/Human health and pathology/Pulmonology and respiratory tract MESH: Methylation MESH: DNA Methylation [SDV.CAN] Life Sciences [q-bio]/Cancer Cell Line Tumor [SDV.BBM] Life Sciences [q-bio]/Biochemistry Molecular Biology Humans methylation signaling MESH: Neoplasms [SDV.BBM]Life Sciences [q-bio]/Biochemistry Molecular Biology Phosphorylation Molecular Biology alkylation E3 ligase SMYD3 MESH: Humans MESH: R-Loop Structures MESH: Transcription Genetic SCLC Histone-Lysine N-Methyltransferase ASCC MESH: RNA Neoplasm Small Cell Lung Carcinoma DNA-Binding Proteins Oncology RNF113A MESH: HEK293 Cells MESH: HeLa Cells RNA methylation [SDV.MHEP.PSR] Life Sciences [q-bio]/Human health and pathology/Pulmonology and respiratory tract MESH: Ubiquitination transcription Protein Processing Post-Translational MESH: Nuclear Proteins genome stability MESH: Spliceosomes MESH: DNA-Binding Proteins |
| Zdroj: | Cancer Discovery Cancer Discovery, In press, ⟨10.1158/2159-8290.CD-21-0205⟩ Cancer Discovery, 12, 2158-2179 Cancer Discovery, 12, 9, pp. 2158-2179 |
| ISSN: | 2159-8290 2159-8274 |
| Popis: | 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 sensitivity and providing a rationale for small-molecule SMYD3 inhibition to improve responses to established chemotherapy. Significance: SCLC rapidly becomes resistant to conventional chemotherapy, leaving patients with no alternative treatment options. Our data demonstrate that SMYD3 upregulation and RNF113A methylation in SCLC are key mechanisms that control the alkylation damage response. Notably, SMYD3 inhibition sensitizes cells to alkylating agents and promotes sustained SCLC response to chemotherapy. This article is highlighted in the In This Issue feature, p. 2007 |
| Databáze: | OpenAIRE |
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