Diverse involvement of EZH2 in cancer epigenetics

Abstract

EZH2 is the catalytic subunit of Polycomb Repressor Complex 2 (PRC2) which catalyzes methylation of histone H3 at lysine 27 (H3K27me) and mediates gene silencing of target genes via local chromatin reorganization. Numerous evidences show that EZH2 plays a critical role in cancer initiation, progression and metastasis, as well as in cancer stem cell biology. Indeed, EZH2 dysregulation alters gene expression programs in various cancer types. The molecular mechanisms responsible for EZH2 alteration appear to be diverse and depending on the type of cancer. Furthermore, accumulating evidences indicate that EZH2 could also act as a PRC2-independent transcriptional activator in cancer. In this review, we address the current understanding of the oncogenic role of EZH2, including the mechanisms of EZH2 dysregulation in cancer and progresses in therapeutic approaches targeting EZH2.

Keywords: EZH2; cancer; cancer stem cells; chromatin modification; histone lysine methylation; polycomb repression.

Figure 1

Schematic representation of the diverse EZH2 dysregulations found in cancer. A. The histone lysine methyltransferase EZH2 catalyzes H3K27 methylation at defined target genes and silences their expression. B. Overabundance of EZH2 is responsible for an increase in H3K27me3 repressive mark levels leading to the silencing of tumor suppressor genes in cancer cells. C. EZH2 bearing activating mutations at residues Y641, A677 or A687 possesses an enhanced activity leading to an increase in H3K27me3 levels. D. Overexpression of EZH2-interacting partners such as specific lncRNAs enhances recruitment of EZH2 to targets and increases H3K27me3 levels. E. EZH2 harboring an inactivating mutation or EZH2 gene deletion leads to a decrease in H3K27me3 levels and activation of EZH2 target gene programs in cancer. F. A lysine to methionine substitution at position 27 (K27M) in the gene encoding histone H3.3 (H3F3A) inhibits EZH2 activity and leads to nearly undetectable H3K27me3 repressive mark levels in pediatric gliomas. Purple hexagons represent H3K27me epigenetic marks, and M illustrates H3.3K27M mutant histones.

Figure 2

Schematic representation of EZH2 overexpression controlling levels. EZH2 overexpression in cancer cells is achieved at the transcriptional level through the binding of transcription factors to its promoter or at the post-transciptional level via the alteration of the micro-RNA regulation.

Figure 3

PRC2-independent transcriptional activation by EZH2 in cancer. A. In ER-positive breast cancer cells, EZH2 interacts with β-catenin and ER, and functionally enhances gene expression. B. In ER-negative breast cancer cells, EZH2 interacts with RELA/RELB to stimulate NF-κB target gene expression. C. In colorectal cancer cells, EZH2 forms a complex with β-catenin and PAF to promote transcription. D. In castration-resistant prostate cancer, AKT1-mediated phosphorylation of EZH2 at serine 21 allows EZH2 to interact with the AR at target genes to activate transcription. The AKT pathway then acts as a molecular switch changing EZH2 function from a chromatin silencer to a transcriptional co-activator of the AR. This transcriptional activation function is methyltransferase activity-dependent. E. AKT1-mediated phosphorylation of EZH2 at serine 21 also facilitates STAT3 methylation and activation in glioblastoma stem cells. ER: estrogen receptor; TCF: T-cell factor; AR: androgen receptor; PAF: PCNA-associated factor; RNA Polase: RNA polymerase II.

Figure 4

Methionine cycle and mode of action of several EZH2 inhibitors. DNZep is an inhibitor of SAH hydrolase leading to an accumulation of SAH which in turn inhibits EZH2 activity, as well as other cellular methltransferases. SAM competitors such as EPZ005687, EPZ-6438, EI1, UNC1999 and GSK126 bind to the SAH-binding pocket of EZH2 to prevent the recruitment of the SAM methyl donor. SAH-EZH2 peptides disrupt the PRC2 assembly required for full EZH2 activity.