NSD1 mediates antagonism between SWI/SNF and polycomb complexes and is required for transcriptional activation upon EZH2 inhibition.
Chromatin
/ genetics
Enhancer of Zeste Homolog 2 Protein
/ antagonists & inhibitors
F-Box Proteins
/ genetics
Histone-Lysine N-Methyltransferase
/ genetics
Histones
/ genetics
Humans
Jumonji Domain-Containing Histone Demethylases
/ genetics
Polycomb-Group Proteins
/ genetics
Rhabdoid Tumor
/ genetics
SMARCB1 Protein
/ genetics
Transcription Factors
/ genetics
Transcriptional Activation
/ genetics
Tumor Cells, Cultured
/ metabolism
BAF
EZH2 inhibition
NSD1
SWI/SNF
chromatin
epigenetics
polycomb
transcription
Journal
Molecular cell
ISSN: 1097-4164
Titre abrégé: Mol Cell
Pays: United States
ID NLM: 9802571
Informations de publication
Date de publication:
07 07 2022
07 07 2022
Historique:
received:
30
09
2021
revised:
03
03
2022
accepted:
11
04
2022
pubmed:
11
5
2022
medline:
14
7
2022
entrez:
10
5
2022
Statut:
ppublish
Résumé
Disruption of antagonism between SWI/SNF chromatin remodelers and polycomb repressor complexes drives the formation of numerous cancer types. Recently, an inhibitor of the polycomb protein EZH2 was approved for the treatment of a sarcoma mutant in the SWI/SNF subunit SMARCB1, but resistance occurs. Here, we performed CRISPR screens in SMARCB1-mutant rhabdoid tumor cells to identify genetic contributors to SWI/SNF-polycomb antagonism and potential resistance mechanisms. We found that loss of the H3K36 methyltransferase NSD1 caused resistance to EZH2 inhibition. We show that NSD1 antagonizes polycomb via cooperation with SWI/SNF and identify co-occurrence of NSD1 inactivation in SWI/SNF-defective cancers, indicating in vivo relevance. We demonstrate that H3K36me2 itself has an essential role in the activation of polycomb target genes as inhibition of the H3K36me2 demethylase KDM2A restores the efficacy of EZH2 inhibition in SWI/SNF-deficient cells lacking NSD1. Together our data expand the mechanistic understanding of SWI/SNF and polycomb interplay and identify NSD1 as the key for coordinating this transcriptional control.
Identifiants
pubmed: 35537449
pii: S1097-2765(22)00326-4
doi: 10.1016/j.molcel.2022.04.015
pmc: PMC9520607
mid: NIHMS1836043
pii:
doi:
Substances chimiques
Chromatin
0
F-Box Proteins
0
Histones
0
Polycomb-Group Proteins
0
SMARCB1 Protein
0
SMARCB1 protein, human
0
Transcription Factors
0
histone H3 trimethyl Lys4
0
Jumonji Domain-Containing Histone Demethylases
EC 1.14.11.-
KDM2A protein, human
EC 1.14.11.27
EZH2 protein, human
EC 2.1.1.43
Enhancer of Zeste Homolog 2 Protein
EC 2.1.1.43
Histone-Lysine N-Methyltransferase
EC 2.1.1.43
NSD1 protein, human
EC 2.1.1.43
Types de publication
Journal Article
Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
2472-2489.e8Subventions
Organisme : NCI NIH HHS
ID : F31 CA261150
Pays : United States
Organisme : NCI NIH HHS
ID : P01 CA196539
Pays : United States
Organisme : NCI NIH HHS
ID : R01 CA113794
Pays : United States
Organisme : NCI NIH HHS
ID : P30 CA021765
Pays : United States
Organisme : NIAID NIH HHS
ID : R01 AI118891
Pays : United States
Organisme : NCI NIH HHS
ID : R01 CA172152
Pays : United States
Informations de copyright
Copyright © 2022 Elsevier Inc. All rights reserved.
Déclaration de conflit d'intérêts
Declaration of interests The authors declare no competing interests.
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