Targeting Enhancer of Zeste Homolog 2 as a promising strategy for cancer treatment

Abstract

Polycomb group proteins represent a global silencing system involved in development regulation. In specific, they regulate the transition from proliferation to differentiation, contributing to stem-cell maintenance and inhibiting an inappropriate activation of differentiation programs. Enhancer of Zeste Homolog 2 (EZH2) is the catalytic subunit of Polycomb repressive complex 2, which induces transcriptional inhibition through the tri-methylation of histone H3, an epigenetic change associated with gene silencing. EZH2 expression is high in precursor cells while its level decreases in differentiated cells. EZH2 is upregulated in various cancers with high levels associated with metastatic cancer and poor prognosis. Indeed, aberrant expression of EZH2 causes the inhibition of several tumor suppressors and differentiation genes, resulting in an uncontrolled proliferation and tumor formation. This editorial explores the role of Polycomb repressive complex 2 in cancer, focusing in particular on EZH2. The canonical function of EZH2 in gene silencing, the non-canonical activities as the methylation of other proteins and the role in gene transcriptional activation, were summarized. Moreover, mutations of EZH2, responsible for an increased methyltransferase activity in cancer, were recapitulated. Finally, various drugs able to inhibit EZH2 with different mechanism were described, specifically underscoring the effects in several cancers, in order to clarify the role of EZH2 and understand if EZH2 blockade could be a new strategy for developing specific therapies or a way to increase sensitivity of cancer cells to standard therapies.

Keywords: Enhancer of Zeste Homolog 2; Polycomb group proteins; Histone methyltransferase; Enhancer of Zeste Homolog 2 inhibitors; Anticancer drugs; Cancer therapy; Epigenetics

Core tip: Epigenetics modifications are key players in differentiation programs and are frequently altered in cancer. Since chromatin changes can be reversed with specific drugs, in the last years several studies explored the possibility to target epigenetics alteration as a new strategy for cancer treatment. This editorial focuses on Enhancer of Zeste Homolog 2 (EZH2), the catalytic subunit of Polycomb repressive complex 2 in cancer, analyzing different roles of this protein in various cancers. Several different classes of EZH2 inhibitors are also highlighted, giving distinct thoughtfulness to small molecules that are now under consideration as potential candidates for cancer treatment alone or in combination with other drugs.