EZH2-H3K27me3 mediated KRT14 upregulation promotes TNBC peritoneal metastasis

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 and Dipak Datta ()
Additional contact information
Ayushi Verma: CSIR-Central Drug Research Institute (CDRI)
Akhilesh Singh: CSIR-Central Drug Research Institute (CDRI)
Manish Pratap Singh: CSIR-Central Drug Research Institute (CDRI)
Mushtaq Ahmad Nengroo: CSIR-Central Drug Research Institute (CDRI)
Krishan Kumar Saini: CSIR-Central Drug Research Institute (CDRI)
Saumya Ranjan Satrusal: CSIR-Central Drug Research Institute (CDRI)
Muqtada Ali Khan: CSIR-Central Drug Research Institute (CDRI)
Priyank Chaturvedi: CSIR-Central Drug Research Institute (CDRI)
Abhipsa Sinha: CSIR-Central Drug Research Institute (CDRI)
Sanjeev Meena: CSIR-Central Drug Research Institute (CDRI)
Anup Kumar Singh: CSIR-Central Drug Research Institute (CDRI)
Dipak Datta: CSIR-Central Drug Research Institute (CDRI)

Nature Communications, 2022, vol. 13, issue 1, 1-22

Abstract: 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.

Date: 2022
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DOI: 10.1038/s41467-022-35059-x

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