Epigenetic silencing of tumor suppressor Par-4 promotes chemoresistance in recurrent breast cancer

The Journal of Clinical Investigation
Nathaniel W MabeJames V Alvarez

Abstract

Tumor relapse is the leading cause of death in breast cancer, largely due to the fact that recurrent tumors are frequently resistant to chemotherapy. We previously reported that downregulation of the proapoptotic protein Par-4 promotes tumor recurrence in genetically engineered mouse models of breast cancer recurrence. In the present study, we examined the mechanism and functional significance of Par-4 downregulation in recurrent tumors. We found that epithelial-to-mesenchymal transition (EMT) promotes epigenetic silencing of Par-4 in recurrent tumors. Par-4 silencing proceeded through binding of the EMT transcription factor Twist to the Par-4 promoter, where Twist induced a unique bivalent chromatin domain. This bivalent configuration conferred plasticity at the Par-4 promoter, and Par-4 silencing could be reversed with pharmacologic inhibitors of Ezh2 and HDAC1/2. Using an epigenome editing approach to reexpress Par-4 by specifically reversing the histone modifications found in recurrent tumors, we found that Par-4 reexpression sensitized recurrent tumors to chemotherapy in vitro and in vivo. Upon reexpression, Par-4 bound to the protein phosphatase PP1, caused widespread changes in phosphorylation of cytoskeletal proteins, a...Continue Reading

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Citations

May 10, 2020·Breast Cancer : the Journal of the Japanese Breast Cancer Society·Yangguang XuChi Zhang
Jun 10, 2019·The FEBS Journal·Andrea M ClarkSteven M Pascal
Oct 11, 2019·Cells·Mohammad Mijanur RahmanTrygve O Tollefsbol
Mar 24, 2021·Developmental Cell·Yoko Katsuno, Rik Derynck
Jun 17, 2021·Epigenetics : Official Journal of the DNA Methylation Society·Mariana Brütt PachecoCarmen Jerónimo
Jul 24, 2021·Scientific Reports·Rachel NewcombJames V Alvarez
Nov 5, 2020·Cell Reports·Nathaniel W MabeJames V Alvarez

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Methods Mentioned

BETA
PCR
RNA-seq
immunoprecipitation
acetylation
ChIP
ChIP-seq
coimmunoprecipitation
transfection
Illumina sequencing

Software Mentioned

Bowtie
MACS2
ActiveMotif
DNASTAR MegAlign
TrimGalore
GSEA
IGV
GraphPad Prism
GraphPad Prism7
ImageStudio Lite

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