Regulation of neuroendocrine plasticity by the RNA-binding protein ZFP36L1.
Journal
Nature communications
ISSN: 2041-1723
Titre abrégé: Nat Commun
Pays: England
ID NLM: 101528555
Informations de publication
Date de publication:
25 08 2022
25 08 2022
Historique:
received:
21
09
2021
accepted:
08
07
2022
entrez:
25
8
2022
pubmed:
26
8
2022
medline:
30
8
2022
Statut:
epublish
Résumé
Some small cell lung cancers (SCLCs) are highly sensitive to inhibitors of the histone demethylase LSD1. LSD1 inhibitors are thought to induce their anti-proliferative effects by blocking neuroendocrine differentiation, but the mechanisms by which LSD1 controls the SCLC neuroendocrine phenotype are not well understood. To identify genes required for LSD1 inhibitor sensitivity in SCLC, we performed a positive selection genome-wide CRISPR/Cas9 loss of function screen and found that ZFP36L1, an mRNA-binding protein that destabilizes mRNAs, is required for LSD1 inhibitor sensitivity. LSD1 binds and represses ZFP36L1 and upon LSD1 inhibition, ZFP36L1 expression is restored, which is sufficient to block the SCLC neuroendocrine differentiation phenotype and induce a non-neuroendocrine "inflammatory" phenotype. Mechanistically, ZFP36L1 binds and destabilizes SOX2 and INSM1 mRNAs, two transcription factors that are required for SCLC neuroendocrine differentiation. This work identifies ZFP36L1 as an LSD1 target gene that controls the SCLC neuroendocrine phenotype and demonstrates that modulating mRNA stability of lineage transcription factors controls neuroendocrine to non-neuroendocrine plasticity.
Identifiants
pubmed: 36008402
doi: 10.1038/s41467-022-31998-7
pii: 10.1038/s41467-022-31998-7
pmc: PMC9411550
doi:
Substances chimiques
Butyrate Response Factor 1
0
RNA-Binding Proteins
0
Repressor Proteins
0
Transcription Factors
0
ZFP36L1 protein, human
0
INSM1 protein, human
147955-03-1
Histone Demethylases
EC 1.14.11.-
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
4998Subventions
Organisme : NCI NIH HHS
ID : K08 CA222657
Pays : United States
Organisme : NCI NIH HHS
ID : P30 CA008748
Pays : United States
Organisme : NCI NIH HHS
ID : R35 CA263816
Pays : United States
Organisme : NCI NIH HHS
ID : R37 CA269990
Pays : United States
Informations de copyright
© 2022. The Author(s).
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