A non-canonical EZH2 function sensitizes solid tumors to genotoxic stress

Abstract

SummaryDrugs that block the activity of the methyltransferase EZH2 are in clinical development for the treatment of non-Hodgkin lymphomas harboring gain-of-function EZH2 mutations that enhance its polycomb repressive function. In contrast, in castration-resistant prostate cancer (CRPC) we have previously reported that EZH2 plays a non-canonical role as a transcriptional activator. In this setting, we now show that EZH2 inhibitors can also block the non-canonical activity of EZH2 and inhibit the growth of CRPC cells. Gene expression and epigenomic profiling of cells treated with EZH2 inhibitors demonstrated that rather than de-repressing tumor suppressor genes silenced by PRC2, EZH2 inhibitors downregulate a set of DNA repair genes that are directly regulated by EZH2. In addition, genome-wide CRISPR/Cas9-mediated loss-of-function screens in the presence of EZH2 inhibitors identified these DNA repair genes to underlie the growth-inhibitory function of these compounds. Interrogation of public data from diverse solid tumor types expressing wild-type EZH2 showed that expression of DNA damage repair genes is significantly correlated with cellular sensitivity to EZH2 inhibitors. Consistent with these findings, treatment of CRPC cells with EZH2 inhibitors dramatically enhanced their sensitivity to genotoxic stress. These studies reveal a previously unappreciated mechanism of action of EZH2 inhibitors and provide a mechanistic basis for potential new combination cancer therapies.

Landscape of immune-related signatures induced by targeting of different epigenetic regulators in melanoma: implications for immunotherapy

“…Taken together, these results significantly extend previous knowledge on non-immuno-related anti-tumor activities of epigenetic inhibitors, such as reactivation of tumor suppressor genes by demethylating agents [47], promotion of cell death and suppression of angiogenesis by HDAC inhibitors [48], inhibition of proto-oncogenes MYC and BCL2 by BET inhibitors [49] and downregulation of DNA repair genes by EZH2 inhibitors [50].…”

“…The drugs affected also expression of genes encoding proteolytic enzymes (cathepsins), and their inhibitors (serpins), thus implicating epigenetic drugs in the regulation of different cancer-related processes, controlled by cathepsins, such as proliferation, angiogenesis, metastasis and invasion. Taken together, these results significantly extend previous knowledge on non-immuno-related anti-tumor activities of epigenetic inhibitors, such as reactivation of tumor suppressor genes by demethylating agents [47], promotion of cell death and suppression of angiogenesis by HDAC inhibitors [48], inhibition of proto-oncogenes MYC and BCL2 by BET inhibitors [49] and downregulation of DNA repair genes by EZH2 inhibitors [50].…”