Defining and Targeting Epigenetic Rewiring During Tumor Progression

Abstract

Tumor recurrence following initial treatment is the leading cause of death among breast cancer patients. Epigenetic mechanisms are critical for regulation of gene expression and to facilitate appropriate responses to environmental cues. However, it is increasingly appreciated that epigenetic dysregulation directly promotes therapeutic resistance and tumor progression. While genetic alterations have been shown to promote tumor progression, the contribution of non-genetic drivers of recurrence remains unexplored. In the current work, we utilized genetically engineered mouse models of breast cancer recurrence to evaluate the contribution of epigenetic plasticity to tumor recurrence and chemoresistance. First, we found that recurrent tumors undergo dramatic epigenetic and transcriptional reprogramming, partially through acquisition of an epithelial-to-mesenchymal transition (EMT). EMT promoted epigenetic silencing of tumor suppressor Par-4 through a unique, bivalent histone configuration. This bivalent configuration conferred plasticity to Par-4, and Par-4 silencing was reversed with epigenetic inhibitors of EHZ2 and HDAC. Further, Par-4 re-expression sensitized recurrent tumors to commonly utilized microtubule-targeting chemotherapeutics through altered cytoskeletal regulation. Second, we found that recurrent tumor epigenetic and transcriptional rewiring conferred sensitivity to G9a inhibitors. G9a inhibition promoted recurrent tumor cell necroptosis through demethylation of genes involved in a pro-inflammatory cytokine program. Further, knockout of G9a protein delayed the time until mammary tumors recurred in vivo. Collectively, our studies demonstrate that epigenetic dysregulation is a key feature of breast cancer progression, and pharmacologic strategies designed to target epigenetic enzymes underlying these processes may be of clinical value in the treatment of recurrent breast cancer.