Dual EZH2 and G9a inhibition suppresses multiple myeloma cell proliferation by regulating the interferon signal and IRF4-MYC axis

Abstract

Epigenetic mechanisms such as histone modification play key roles in the pathogenesis of multiple myeloma (MM). We previously showed that EZH2, a histone H3 lysine 27 (H3K27) methyltransferase, and G9, a H3K9 methyltransferase, are potential therapeutic targets in MM. Moreover, recent studies suggest EZH2 and G9a cooperate to regulate gene expression. We therefore evaluated the antitumor effect of dual EZH2 and G9a inhibition in MM. A combination of an EZH2 inhibitor and a G9a inhibitor strongly suppressed MM cell proliferation in vitro by inducing cell cycle arrest and apoptosis. Dual EZH2/G9a inhibition also suppressed xenograft formation by MM cells in vivo. In datasets from the Gene Expression Omnibus, higher EZH2 and EHMT2 (encoding G9a) expression was significantly associated with poorer prognoses in MM patients. Microarray analysis revealed that EZH2/G9a inhibition significantly upregulated interferon (IFN)-stimulated genes and suppressed IRF4-MYC axis genes in MM cells. Notably, dual EZH2/G9a inhibition reduced H3K27/H3K9 methylation levels in MM cells and increased expression of endogenous retrovirus (ERV) genes, which suggests that activation of ERV genes may induce the IFN response. These results suggest that dual targeting of EZH2 and G9a may be an effective therapeutic strategy for MM.

Targeting Myc Interacting Proteins as a Winding Path in Cancer Therapy

“…Deficiency of G9a reduces c-Myc binding activity to promoters and inhibits glioblastoma cell proliferation and tumorigenesis ability ( Ke et al, 2020 ). Dual EZH2 and G9a inhibition suppresses multiple myeloma (MM) cell proliferation through the IRF4-Myc axis ( Ishiguro et al, 2021 ). It is worth mentioning that Myc-G9a repress gene transcription in Miz-1-independent manner, this reminds that G9a is necessary for Myc chromatin-binding and gene repression ( Tu et al, 2018 ).…”

Investigating the Interplay between Myeloma Cells and Bone Marrow Stromal Cells in the Development of Drug Resistance: Dissecting the Role of Epigenetic Modifications

“…Higher expression levels of DOT1L were detected, especially in the early stages of multiple myeloma, MGUS and smoldering multiple myeloma (SMM). The inhibition of DOT1L was able to block the proliferation of myeloma cells in in vitro models [86,87].…”

Histone Methylation Related Therapeutic Challenge in Cardiovascular Diseases

“…G9a is responsible for the homeostasis of cardiomyocytes by mediating H3K9 dimethylation to inhibit the expression of cardiomyocyte-related genes and the formation of a complex with EZH2 and MEF2C ( 149 ). TAC mice, which were administered with BIX-01294 (a G9a inhibitor), had improved cardiac function and prevented the development of hypertrophy ( 150 ).…”