SMYD3 Impedes Small Cell Lung Cancer Sensitivity to Alkylation Damage through RNF113A Methylation-Phosphorylation Cross-talk

• Published in: Cancer discovery 2022-09, Vol.12 (9), p.2158-2179
• Main Authors: Lukinović, Valentina, Hausmann, Simone, Roth, Gael S, Oyeniran, Clement, Ahmad, Tanveer, Tsao, Ning, Brickner, Joshua R, Casanova, Alexandre G, Chuffart, Florent, Benitez, Ana Morales, Vayr, Jessica, Rodell, Rebecca, Tardif, Marianne, Jansen, Pascal W T C, Couté, Yohann, Vermeulen, Michiel, Hainaut, Pierre, Mazur, Pawel K, Mosammaparast, Nima, Reynoird, Nicolas
• Format: Article
• Language: English
• Subjects: AlkB Homolog 3, Alpha-Ketoglutarate-Dependent Dioxygenase; Alkylation; Biochemistry, Molecular Biology; Cancer; Cell Line, Tumor; Cell Nucleus; DNA Helicases; DNA Methylation; DNA-Binding Proteins; DNA-Binding Proteins - metabolism; HEK293 Cells; HeLa Cells; Histone-Lysine N-Methyltransferase - genetics; Histone-Lysine N-Methyltransferase - metabolism; Human health and pathology; Humans; Life Sciences; Lung Neoplasms - drug therapy; Lung Neoplasms - genetics; Methylation; Neoplasms; Nuclear Proteins; Phosphorylation; Protein Processing, Post-Translational; Pulmonology and respiratory tract; R-Loop Structures; RNA Processing, Post-Transcriptional; RNA, Neoplasm; Small Cell Lung Carcinoma - drug therapy; Small Cell Lung Carcinoma - genetics; Spliceosomes; Transcription, Genetic; Ubiquitination
• ISSN: 2159-8274; 2159-8290
• DOI: 10.1158/2159-8290.CD-21-0205

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. 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.