Epigenetic regulation of cancer biology and anti-tumor immunity by EZH2

Abstract

Polycomb group proteins regulate chromatin structure and have an important regulatory role on gene expression in various cell types. Two polycomb group complexes (Polycomb repressive complex 1 (PRC1) and 2 (PRC2)) have been identified in mammalian cells. Both PRC1 and PRC2 compact chromatin, and also catalyze histone modifications. PRC1 mediates monoubiquitination of histone H2A, whereas PRC2 catalyzes methylation of histone H3 on lysine 27. These alterations of histones can lead to altered gene expression patterns by regulating chromatin structure. Numerous studies have highlighted the role of the PRC2 catalytic component enhancer of zeste homolog 2 (EZH2) in neoplastic development and progression, and EZH2 mutations have been identified in various malignancies. Through modulating the expression of critical genes, EZH2 is actively involved in fundamental cellular processes such as cell cycle progression, cell proliferation, differentiation and apoptosis. In addition to cancer cells, EZH2 also has a decisive role in the differentiation and function of T effector and T regulatory cells. In this review we summarize the recent progress regarding the role of EZH2 in human malignancies, highlight the molecular mechanisms by which EZH2 aberrations promote the pathogenesis of cancer, and discuss the anti-tumor effects of EZH2 targeting via activating direct anti-cancer mechanisms and anti-tumor immunity.

E2F4 functions as a tumour suppressor in acute myeloid leukaemia via inhibition of the MAPK signalling pathway by binding to EZH2

“…13,46 Though down-regulation and loss-of-function mutations suggest tumour-suppressive activity of EZH2 in some cancers, there is evidence to demonstrate that EZH2 with gain-offunction mutations acts as an oncogene in numerous other cancers, such as prostate cancer and breast cancer (BC). A-C, Tumour images and weights at experimental end-points in NC and shE2F4 NB4 xenografts (n = 5 for each group).…”

“…12,13 E2F4 is a transcription factor (TF) that contributes to controlling the cell cycle. Members of the E2F family contain many important genes that regulate the cell cycle, DNA damage repair and development.…”

Aberrant expression of p16INK4a in human cancers – a new biomarker?

“…2). The PRC2 complex is composed of three core proteins, EZH2 which mediates tri-methylation of histone H3K27, EED, SUZ12, and RbAp46 (49; Fig. 2).…”

“…Histone methyltransferase EZH2 plays a critical role in epigenetic regulation as a bridge between histone methylation/deacetylation and DNA methylation. EZH2 is frequently overexpressed and considered to be an oncogene in cancers (49). The SET domain of EZH2 possesses methyltransferase activity specific for histone H3K27 (50, 51).…”

“…The most important mechanism for transcriptional repression by the PRC1 complex involves mono-ubiquitination of histone H2A K119 by histone H2A ubiquitin ligase (48). The PRC2 complex is composed of three core proteins, EZH2 which mediates tri-methylation of histone H3K27, EED, SUZ12, and RbAp46 (49). …”