Improved Therapeutic Effect against Leukemia by a Combination of the Histone Methyltransferase Inhibitor Chaetocin and the Histone Deacetylase Inhibitor Trichostatin A

Abstract

SUV39H1 is a histone 3 lysine 9 (H3K9)-specific methyltransferase that is important for heterochromatin formation and the regulation of gene expression. Chaetocin specifically inhibits SUV39H1, resulted in H3K9 methylation reduction as well as reactivation of silenced genes in cancer cells. Histone deacetylase (HDAC) inhibitors inhibit deacetylases and accumulate high levels of acetylation lead to cell cycle arrest and apoptosis. In this study, we demonstrated that treatment with chaetocin enhanced apoptosis in human leukemia HL60, KG1, Kasumi, K562, and THP1 cells. In addition, chaetocin induced the expression of cyclin-dependent kinase inhibitor 2B (p15), E-cadherin (CDH1) and frizzled family receptor 9 (FZD9) through depletion of SUV39H1 and reduced H3K9 methylation in their promoters. Co-treatment with chaetocin and HDAC inhibitor trichostatin A (TSA) dramatically increased apoptosis and produced greater activation of genes. Furthermore, this combined treatment significantly increased loss of SUV39H1 and reduced histone H3K9 trimethylation responses accompanied by increased acetylation. Importantly, co-treatment with chaetocin and TSA produced potent antileukemic effects in leukemia cells derived from patients. These in vitro findings suggest that combination therapy with SUV39H1 and HDAC inhibitors may be of potential value in the treatment of leukemia.

Histone lysine methyltransferase SUV39H1 is a potent target for epigenetic therapy of hepatocellular carcinoma

“…In this study, chaetocin remarkably suppressed the tumorigenicity of HCC cells in culture and in a xenograft transplantation model. Chaetocin reduced H3K9me3 levels as well as SUV39H1 levels in a dose‐dependent manner in HCC cells, which was also reported for human leukemic cells …”

“…Chaetocin reduced H3K9me3 levels as well as SUV39H1 levels in a dose-dependent manner in HCC cells, which was also reported for human leukemic cells. 31 Although the pharmacological mechanism of chaetocin has not yet been completely elucidated, chaetocin might have a direct effect to reduce the SUV39H1 protein. Considering that chaetocin was found to modulate the expression of various cancer-related genes, 32,33 another possibility is that altered expressions of these genes might cause a secondary downregulation of SUV39H1.…”

Molecular Pathways: Metabolic Control of Histone Methylation and Gene Expression in Cancer

“…Chaetocin is an inhibitor that inhibits methyltransferase Suv39h1 and reduces H3K9 repressive markers (78). Chaetocin treatment in human leukemia cells inhibits H3K9 methylation and reactivates the expression of E-cadherin and tumor suppressor p15 (79, 80). Further studies are needed to investigate the effect of H3K9-specific methyltransferase inhibitors on gene expression and the therapeutic response of cancer cells during hypoxia.…”

The SUV39H1 inhibitor chaetocin induces differentiation and shows synergistic cytotoxicity with other epigenetic drugs in acute myeloid leukemia cells

“…Two recent studies demonstrated that chaetocin in addition to inhibit SUV39H1 enzymatic activity also reduced protein level of this methyltransferase. 28 , 29 One of the studies revealed that chaetocin at high concentration acts as a heat shock protein 90 (HSP90) inhibitor and induces degradation of a number of HSP90 client proteins including SUV39H1. 29 These results make the story of chaetocin more complex and suggest that anti-cancer action of chaetocin is time, dose and cell-context dependent.…”