SMYD3 Impedes Small Cell Lung Cancer Sensitivity to Alkylation Damage through RNF113A Methylation–Phosphorylation Cross-talk - Archive ouverte HAL Access content directly
Journal Articles Cancer Discovery Year : 2022

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

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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
Pascal W.T.C. Jansen
Yohann Couté
Michiel Vermeulen
Pierre Hainaut
Pawel K Mazur
Nima Mosammaparast
Nicolas Reynoird
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Abstract

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.
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Origin : Publication funded by an institution

Dates and versions

hal-03759864 , version 1 (25-08-2022)

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Valentina Lukinović, Simone Hausmann, Gael S Roth, Clement Oyeniran, Tanveer Ahmad, et al.. SMYD3 Impedes Small Cell Lung Cancer Sensitivity to Alkylation Damage through RNF113A Methylation–Phosphorylation Cross-talk. Cancer Discovery, In press, ⟨10.1158/2159-8290.CD-21-0205⟩. ⟨hal-03759864⟩
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