EZH2 Inhibition Sensitizes CARM1-High, Homologous Recombination Proficient Ovarian Cancers to PARP Inhibition.
Antineoplastic Agents
/ therapeutic use
DNA Breaks, Double-Stranded
/ drug effects
DNA End-Joining Repair
/ drug effects
Enhancer of Zeste Homolog 2 Protein
/ antagonists & inhibitors
Enzyme Inhibitors
/ therapeutic use
Female
Homologous Recombination
/ drug effects
Humans
Ovarian Neoplasms
/ drug therapy
Poly(ADP-ribose) Polymerase Inhibitors
/ pharmacology
Protein-Arginine N-Methyltransferases
/ drug effects
Recombinational DNA Repair
/ drug effects
BAF155
CARM1
EZH2 inhibitors
MAD2L2 (REV7)
PARP inhibitors
SWI/SNF
epithelial ovarian cancer
homologous recombination (HR)
non-homologous end-joining (NHEJ)
polycomb repressive complex 2 (PRC2)
shieldin
Journal
Cancer cell
ISSN: 1878-3686
Titre abrégé: Cancer Cell
Pays: United States
ID NLM: 101130617
Informations de publication
Date de publication:
10 02 2020
10 02 2020
Historique:
received:
28
01
2019
revised:
23
10
2019
accepted:
30
12
2019
pubmed:
1
2
2020
medline:
22
7
2020
entrez:
1
2
2020
Statut:
ppublish
Résumé
In response to DNA double-strand breaks, MAD2L2-containing shieldin complex plays a critical role in the choice between homologous recombination (HR) and non-homologous end-joining (NHEJ)-mediated repair. Here we show that EZH2 inhibition upregulates MAD2L2 and sensitizes HR-proficient epithelial ovarian cancer (EOC) to poly(adenosine diphosphate-ribose) polymerase (PARP) inhibitor in a CARM1-dependent manner. CARM1 promotes MAD2L2 silencing by driving the switch from the SWI/SNF complex to EZH2 through methylating the BAF155 subunit of the SWI/SNF complex on the MAD2L2 promoter. EZH2 inhibition upregulates MAD2L2 to decrease DNA end resection, which increases NHEJ and chromosomal abnormalities, ultimately causing mitotic catastrophe in PARP inhibitor treated HR-proficient cells. Significantly, EZH2 inhibitor sensitizes CARM1-high, but not CARM-low, EOCs to PARP inhibitors in both orthotopic and patient-derived xenografts.
Identifiants
pubmed: 32004442
pii: S1535-6108(19)30585-9
doi: 10.1016/j.ccell.2019.12.015
pmc: PMC7155421
mid: NIHMS1569396
pii:
doi:
Substances chimiques
Antineoplastic Agents
0
Enzyme Inhibitors
0
Poly(ADP-ribose) Polymerase Inhibitors
0
Protein-Arginine N-Methyltransferases
EC 2.1.1.319
coactivator-associated arginine methyltransferase 1
EC 2.1.1.319
EZH2 protein, human
EC 2.1.1.43
Enhancer of Zeste Homolog 2 Protein
EC 2.1.1.43
Types de publication
Journal Article
Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't
Research Support, U.S. Gov't, Non-P.H.S.
Langues
eng
Sous-ensembles de citation
IM
Pagination
157-167.e6Subventions
Organisme : NIH HHS
ID : S10 OD021669
Pays : United States
Organisme : NCI NIH HHS
ID : P30 CA010815
Pays : United States
Organisme : NCI NIH HHS
ID : P50 CA228991
Pays : United States
Organisme : NCI NIH HHS
ID : R50 CA211199
Pays : United States
Organisme : NCI NIH HHS
ID : R01 CA202919
Pays : United States
Organisme : NCI NIH HHS
ID : R01 CA239128
Pays : United States
Organisme : NCI NIH HHS
ID : R01 CA160331
Pays : United States
Organisme : NCI NIH HHS
ID : R01 CA163377
Pays : United States
Commentaires et corrections
Type : CommentIn
Informations de copyright
Copyright © 2019 Elsevier Inc. All rights reserved.
Déclaration de conflit d'intérêts
Declaration of Interests S.K. and R.Z. are co-inventors on a patent application covering the use of EZH2 inhibitors in CARM1-expressing cancers. All other authors declare no competing interests.
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