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

Authors

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

Publication Date

9-2-2022

Journal

Cancer Discovery

DOI

10.1158/2159-8290.CD-21-0205

PMID

35819319

PMCID

PMC9437563

PubMedCentral® Posted Date

7-12-2022

PubMedCentral® Full Text Version

Post-print

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. This article is highlighted in the In This Issue feature, p. 2007.

Keywords

Alkylation, Cell Line, Tumor, DNA-Binding Proteins, Histone-Lysine N-Methyltransferase, Humans, Lung Neoplasms, Methylation, Phosphorylation, Protein Processing, Post-Translational, Small Cell Lung Carcinoma

Published Open-Access

yes

Recommended Citation

Lukinović, Valentina; Hausmann, Simone; Roth, Gael S; et al., "SMYD3 Impedes Small Cell Lung Cancer Sensitivity to Alkylation Damage through RNF113A Methylation-Phosphorylation Cross-talk" (2022). Faculty, Staff and Student Publications. 4811.
https://digitalcommons.library.tmc.edu/uthgsbs_docs/4811