Epigenetic Co-Deregulation of EZH2/TET1 is a Senescence-Countering, Actionable Vulnerability in Triple-Negative Breast Cancer

Theranostics
Yong YuRan Tao

Abstract

Triple-negative breast cancer (TNBC) cells lack the expression of ER, PR and HER2. Thus, TNBC patients cannot benefit from hormone receptor-targeted therapy as non-TNBC patients, but can only receive chemotherapy as the systemic treatment and have a worse overall outcome. More effective therapeutic targets and combination therapy strategies are urgently needed to improve the treatment effectiveness. Methods: We analyzed the expression levels of EZH2 and TET1 in TCGA and our own breast cancer patient cohort, and tested their correlation with patient survival. We used TNBC and non-TNBC cell lines and mouse xenograft tumor model to unveil novel EZH2 targets and investigated the effect of EZH2 inhibition or TET1 overexpression in cell proliferation and viability of TNBC cells. Results: In TNBC cells, EZH2 decreases TET1 expression by H3K27me3 epigenetic regulation and subsequently suppresses anti-tumor p53 signaling pathway. Patients with high EZH2 and low TET1 presented the poorest survival outcome. Experimentally, targeting EZH2 in TNBC cells with specific inhibitor GSK343 or shRNA genetic approach could induce cell cycle arrest and senescence by elevating TET1 expression and p53 pathway activation. Using mouse xenograft model, w...Continue Reading

Citations

Aug 21, 2019·Cancers·Rakesh KumarM Radhakrishna Pillai
May 13, 2020·Cancer Metastasis Reviews·Alejandra I FerrerPranela Rameshwar
Jul 30, 2020·Journal of Cellular and Molecular Medicine·Xueliang ZhouXinwei Han
Mar 11, 2021·PloS One·Laura V BownesElizabeth A Beierle
Jul 3, 2021·Pharmaceuticals·Shoghag Panjarian, Jean-Pierre J Issa
Oct 2, 2021·Frontiers in Cell and Developmental Biology·Wei LiDa Pang

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Datasets Mentioned

BETA
HY-15142
MDA-MB-231
GSE112378

Methods Mentioned

BETA
xenograft
immunoprecipitation
ChIP
PCR
dot blot

Software Mentioned

DESeq
GSEA
Guava CytoSoft
STAR
Graphpad Prism
Gene Set Enrichment Analysis ( GSEA )

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