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 August 27, 2018
Citation Information: J Clin Invest. 2018;128(10):4413-4428. https://doi.org/10.1172/JCI99481.
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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

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Figure 6

Par-4 reexpression sensitizes recurrent tumor cells to microtubule-targeting drugs.

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Par-4 reexpression sensitizes recurrent tumor cells to microtubule-targe...
(A) Kaplan-Meier survival curves for mice injected with recurrent tumor cell line 1 (black) or primary tumor cell line 1 (red) and treated with the chemotherapy regimen AC+T (n = 12 recurrent tumors, n = 9 primary tumors) or vehicle (n = 6 recurrent tumors, n = 8 primary tumors). Significance was evaluated using the Mantel-Cox log-rank test. (B and C) Concentration response curves for recurrent tumor cell line 1 with inducible Par-4 expression treated with increasing concentrations of docetaxel (B) or vincristine (C) in the absence (–Shld1) or presence (+Shld1) of Par-4 expression. The IC50 is shown with 95% confidence intervals. Significance was evaluated by Student’s unpaired t test. (D) Cell viability of recurrent tumor cell line 1 with inducible Par-4 expression (top) treated with vehicle (left), 10 nM docetaxel (middle), or 8 nM vincristine (right) in the absence (–Shld1) or presence (+Shld1) of Par-4 expression. Recurrent tumor cells with inducible YFP expression (bottom) are shown to control for the effects of Shld1 administration. (E and F) Growth curves for recurrent tumor cell treated with either 10 nM docetaxel (E) or 8 nM vincristine (F) in the absence (–Shld1) or presence (+Shld1) of Par-4 expression. Significance was evaluated by 3-way ANOVA (Shld1 × drug × time). Asterisks show statistical significance between drug treatment with or without Shld1. Error bars denote mean ± SEM. *P < 0.05, **P < 0.01, ***P < 0.001.