EZH2 synergizes with BRD4-NUT to drive NUT carcinoma growth through silencing of key tumor suppressor genes.
Journal
bioRxiv : the preprint server for biology
Titre abrégé: bioRxiv
Pays: United States
ID NLM: 101680187
Informations de publication
Date de publication:
16 Aug 2023
16 Aug 2023
Historique:
medline:
30
8
2023
pubmed:
30
8
2023
entrez:
30
8
2023
Statut:
epublish
Résumé
NUT carcinoma (NC) is an aggressive carcinoma driven by the BRD4-NUT fusion oncoprotein, which activates chromatin to promote expression of pro-growth genes. BET bromodomain inhibitors (BETi) impede BRD4-NUT's ability to activate genes and are thus a promising treatment but limited as monotherapy. The role of gene repression in NC is unknown. Here, we demonstrate that EZH2, which silences genes through establishment of repressive chromatin, is a dependency in NC. Inhibition of EZH2 with the clinical compound tazemetostat (taz) potently blocked growth of NC cells. Epigenetic and transcriptomic analysis revealed that taz reversed the EZH2-specific H3K27me3 silencing mark, and restored expression of multiple tumor suppressor genes while having no effect on key oncogenic BRD4- NUT-regulated genes. Identification of EZH2 as a dependency in NC substantiates the reliance of NC tumor cells on epigenetic dysregulation of functionally opposite, yet highly complementary chromatin regulatory pathways to maintain NC growth. In particular, repression of CDKN2A expression by EZH2 provides a mechanistic rationale for combining EZH2i with BETi for the clinical treatment of NC.
Identifiants
pubmed: 37645799
doi: 10.1101/2023.08.15.553204
pmc: PMC10461970
pii:
doi:
Types de publication
Preprint
Langues
eng
Subventions
Organisme : NIH HHS
ID : DP5 OD024587
Pays : United States
Organisme : NCI NIH HHS
ID : R01 CA124633
Pays : United States
Organisme : NCI NIH HHS
ID : R35 CA210030
Pays : United States
Commentaires et corrections
Type : UpdateIn
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