Back to Search Start Over

EZH2-H3K27me3 mediated KRT14 upregulation promotes TNBC peritoneal metastasis

Authors :
Ayushi Verma
Akhilesh Singh
Manish Pratap Singh
Mushtaq Ahmad Nengroo
Krishan Kumar Saini
Saumya Ranjan Satrusal
Muqtada Ali Khan
Priyank Chaturvedi
Abhipsa Sinha
Sanjeev Meena
Anup Kumar Singh
Dipak Datta
Source :
Nature communications. 13(1)
Publication Year :
2021

Abstract

Triple-Negative Breast Cancer (TNBC) has a poor prognosis and adverse clinical outcomes among all breast cancer subtypes as there is no available targeted therapy. Overexpression of Enhancer of zeste homolog 2 (EZH2) has been shown to correlate with TNBC’s poor prognosis, but the contribution of EZH2 catalytic (H3K27me3) versus non-catalytic EZH2 (NC-EZH2) function in TNBC progression remains elusive. We reveal that selective hyper-activation of functional EZH2 (H3K27me3) over NC-EZH2 alters TNBC metastatic landscape and fosters its peritoneal metastasis, particularly splenic. Instead of H3K27me3-mediated repression of gene expression; here, it promotes KRT14 transcription by attenuating binding of repressor SP1 to its promoter. Further, KRT14 loss significantly reduces TNBC migration, invasion, and peritoneal metastasis. Consistently, human TNBC metastasis displays positive correlation between H3K27me3 and KRT14 levels. Finally, EZH2 knockdown or H3K27me3 inhibition by EPZ6438 reduces TNBC peritoneal metastasis. Altogether, our preclinical findings suggest a rationale for targeting TNBC with EZH2 inhibitors.

Details

ISSN :
20411723
Volume :
13
Issue :
1
Database :
OpenAIRE
Journal :
Nature communications
Accession number :
edsair.doi.dedup.....7306629b04ea85ca929fe0ad759ce970