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

Y-S Lai,H-J Tsai,T-Y Chen,J-Y Chen,W-C Hung

doi:10.1038/bcj.2015.37

Abstract

Epigenetic modifying enzymes have a crucial role in the pathogenesis of acute myeloid leukemia (AML). Methylation of lysine 9 on histone H3 by the methyltransferase G9a and SUV39H1 is associated with inhibition of tumor suppressor genes. We studied the effect of G9a and SUV39H1 inhibitors on viability and differentiation of AML cells and tested the cytotoxicity induced by combination of G9a and SUV39H1 inhibitors and various epigenetic drugs. The SUV39H1 inhibitor (chaetocin) and the G9a inhibitor (UNC0638) caused cell death in AML cells at high concentrations. However, only chaetocin-induced CD11b expression and differentiation of AML cells at non-cytotoxic concentration. HL-60 and KG-1a cells were more sensitive to chaetocin than U937 cells. Long-term incubation of chaetocin led to downregulation of SUV39H1 and reduction of H3K9 tri-methylation in HL-60 and KG-1a cells. Combination of chaetocin with suberoylanilide hydroxamic acid (SAHA, a histone deacetylase inhibitor) or JQ (a BET (bromodomain extra terminal) bromodomain inhibitor) showed synergistic cytotoxicity. Conversely, no synergism was found by combining chaetocin and UNC0638. More importantly, chaetocin-induced differentiation and combined cytotoxicity were also found in the primary cells of AML patients. Collectively, the SUV39H1 inhibitor chaetocin alone or in combination with other epigenetic drugs may be effective for the treatment of AML.

Highlights

Epigenetic alterations contribute to the pathogenesis of hematopoietic malignancies including acute myeloid leukemia (AML)
We examined the expression of G9a and SUV39H1 in three AML cell lines
These data suggested that chaetocin and UNC0638 showed cytotoxicity in AML cells at high concentration and chaetocin is more potent than UNC0638 in cell killing

Summary

Introduction

Epigenetic alterations contribute to the pathogenesis of hematopoietic malignancies including acute myeloid leukemia (AML). Aberrant promoter methylation inactivates the expression of tumor suppressor genes which leads to blockage of differentiation and deregulated proliferation.[1,2] Targeting the epigenetic modifying enzymes like DNA methyltransferases, histone methyltransferases or histone deacetylase (HDAC) becomes an important area for the development of anti-cancer drugs.[3,4] Currently, several epigenetic drugs have been approved for cancer treatment. The HDAC inhibitors SAHA ( known as Vorinostat) and Romidepsin (Istodax) are used for the treatment of cutaneous T-cell lymphoma. The DNA methyltransferase inhibitors 5ʹazacitidine (Vidaza) and decitabine (Dacogen) are therapeutic drugs for myelodysplastic syndrome

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