Epigenetic silencing of tumor suppressor Par-4 promotes chemoresistance in recurrent breast cancer
Nathaniel W. Mabe, … , J. Will Thompson, James V. Alvarez
Nathaniel W. Mabe, … , J. Will Thompson, James V. Alvarez
Published October 1, 2018; First published August 27, 2018
Citation Information: J Clin Invest. 2018;128(10):4413-4428. https://doi.org/10.1172/JCI99481.
View: Text | PDF
Research Article Oncology

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

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, and cooperated with microtubule-targeting drugs to induce mitotic defects. These results identify Twist-induced epigenetic silencing of Par-4 as a targetable axis that promotes chemoresistance in recurrent breast cancer.

Authors

Nathaniel W. Mabe, Douglas B. Fox, Ryan Lupo, Amy E. Decker, Stephanie N. Phelps, J. Will Thompson, James V. Alvarez

×

Figure 1

Recurrent tumors downregulate Par-4 and undergo EMT.

Options: View larger image (or click on image) Download as PowerPoint
Recurrent tumors downregulate Par-4 and undergo EMT. (A) Representative ...
(A) Representative tumor volume curves showing primary tumor formation following dox administration, tumor regression following dox withdrawal, and spontaneous tumor recurrence in MTB;TAN mice. (B) Kaplan-Meier plots showing recurrence-free survival following doxycycline withdrawal in a large cohort (n = 39) of MTB;TAN tumors. (C) qPCR analysis of the Her2/neu transgene in primary (n = 7) and recurrent (n = 7) MTB;TAN tumors. (D) Western blot showing the expression of Par-4 and EMT markers in a panel of primary and recurrent MTB;TAN tumors. (E) qPCR analysis of Par-4 in primary (n = 7) and recurrent (n = 7) MTB;TAN tumors. (F) Western blot showing the expression of Par-4 and EMT markers in cultured cells derived from primary and recurrent MTB;TAN tumors. (G) Representative micrographs (original magnification: ×10) of primary and recurrent tumor cells showing morphological evidence of EMT in recurrent tumor cells. Error bars denote mean ± SEM, ***P < 0.001. Significance determined by Student’s t test.