Targeting EZH2 in Multiple Myeloma-Multifaceted Anti-Tumor Activity

Abstract

The enhancer of zeste homolog 2 (EZH2) is the enzymatic subunit of the polycomb repressive complex 2 (PRC2) that exerts important functions during normal development as well as disease. PRC2 through EZH2 tri-methylates histone H3 lysine tail residue 27 (H3K27me3), a modification associated with repression of gene expression programs related to stem cell self-renewal, cell cycle, cell differentiation, and cellular transformation. EZH2 is deregulated and subjected to gain of function or loss of function mutations, and hence functions as an oncogene or tumor suppressor gene in a context-dependent manner. The development of highly selective inhibitors against the histone methyltransferase activity of EZH2 has also contributed to insight into the role of EZH2 and PRC2 in tumorigenesis, and their potential as therapeutic targets in cancer. EZH2 can function as an oncogene in multiple myeloma (MM) by repressing tumor suppressor genes that control apoptosis, cell cycle control and adhesion properties. Taken together these findings have raised the possibility that EZH2 inhibitors could be a useful therapeutic modality in MM alone or in combination with other targeted agents in MM. Therefore, we review the current knowledge on the regulation of EZH2 and its biological impact in MM, the anti-myeloma activity of EZH2 inhibitors and their potential as a targeted therapy in MM.

Keywords: EZH2; epigenetic therapy; epigenetics; multiple myeloma.

Figure 1.

Enhancer of zeste homolog 2 (EZH2) expression increases during multiple myeloma (MM) progression. Analysis of EZH2 expression in two MM studies available in Oncomine database [103]. (A) Shows the increase in mean expression of EZH2 in smoldering multiple myeloma (SMM) compared with normal and monoclonal gammopathy of undetermined significance (MGUS) [104]. (B) Mean EZH2 expression is significantly higher in MM and plasma cell leukemia (PCL) patients compared to normal and MGUS [105]. The numbers in the brackets represent the number of patients in each category. n.s. p > 0.05, * p-value < 0.05; ** p-value < 0.01.

Figure 2.

EZH2 expression and activity is regulated at multiple levels in MM. EZH2 expression is regulated by multiple essential oncogenic transcription factors and tumor suppressor microRNAs in MM. EZH2 enzymatic activity is regulated by Ser21 phosphorylation mediated by Akt kinase that function downstream of insulin-like growth factor-1 receptor (IGF-1R) and phosphoinositide 3 (PI3) kinase signaling pathways.

Figure 3.

EZH2 inhibitors demonstrate multifaceted anti-myeloma activity by affecting the malignant plasma cells and the bone marrow microenvironment. XIAP: X-linked inhibitor of apoptosis; MCL1: MCL1, BCL2 family apoptosis regulator; BID: BH3 interacting domain death agonist; BIM: also known as BCL2L11 (BCL2 like 11). BAX: BCL2 associated X, apoptosis regulator. CDKN2B: cyclin dependent kinase inhibitor 2B; CDKN1A: cyclin dependent kinase inhibitor 1A; IRF4: interferon regulatory factor 4; XBP1 X-box binding protein 1; BLIMP-1: also known as PRDM1 (PR/SET domain 1); CDH1: Cadherin 1; EMP1: Epithelial membrane protein 1; VCAN: Versican; EPHB2: Ephrin receptor B2; ENPP1: Ectonucleotide pyrophosphatase/phosphodiesterase 1; RUNX2: Runt related transcription factor 2; OP: Osteopontin; OC: Osteocalcin.