SMYD3 Impedes Small Cell Lung Cancer Sensitivity to Alkylation Damage through RNF113A Methylation-Phosphorylation Cross-talk.
Journal
Cancer discovery
ISSN: 2159-8290
Titre abrégé: Cancer Discov
Pays: United States
ID NLM: 101561693
Informations de publication
Date de publication:
02 09 2022
02 09 2022
Historique:
received:
14
02
2021
revised:
16
02
2022
accepted:
07
07
2022
pubmed:
13
7
2022
medline:
9
9
2022
entrez:
12
7
2022
Statut:
ppublish
Résumé
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.
Identifiants
pubmed: 35819319
pii: 706985
doi: 10.1158/2159-8290.CD-21-0205
pmc: PMC9437563
mid: NIHMS1826425
doi:
Substances chimiques
DNA-Binding Proteins
0
RNF113A protein, human
0
Histone-Lysine N-Methyltransferase
EC 2.1.1.43
SMYD3 protein, human
EC 2.1.1.43
Types de publication
Journal Article
Research Support, Non-U.S. Gov't
Research Support, N.I.H., Extramural
Langues
eng
Sous-ensembles de citation
IM
Pagination
2158-2179Subventions
Organisme : NCI NIH HHS
ID : P01 CA092584
Pays : United States
Organisme : NCI NIH HHS
ID : K99 CA255936
Pays : United States
Organisme : NCI NIH HHS
ID : R01 CA236118
Pays : United States
Organisme : NCI NIH HHS
ID : R01 CA193318
Pays : United States
Organisme : NCI NIH HHS
ID : P50 CA070907
Pays : United States
Organisme : NCI NIH HHS
ID : R01 CA236949
Pays : United States
Organisme : NCI NIH HHS
ID : R01 CA227001
Pays : United States
Informations de copyright
©2022 The Authors; Published by the American Association for Cancer Research.
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