Histone deacetylases 1 and 2 cooperate in regulating BRCA1, CHK1, and RAD51 expression in acute myeloid leukemia cells.

Jianyun Zhao,Holly Edwards,Guan Wang,Chengzhi Xie,Jeffrey W Taub,Yubin Ge

doi:10.18632/oncotarget.14062

Abstract

Resistance to chemotherapy and a high relapse rate highlight the importance of finding new therapeutic options for the treatment of acute myeloid leukemia (AML). Histone deacetylase (HDAC) inhibitors (HDACIs) are a promising class of drugs for the treatment of AML. HDACIs have limited single-agent clinical activities, but when combined with conventional or investigational drugs they have demonstrated favorable outcomes. Previous studies have shown that decreasing expression of important DNA damage repair proteins enhances standard chemotherapy drugs. In our recent studies, the pan-HDACI panobinostat has been shown to enhance conventional chemotherapy drugs cytarabine and daunorubicin in AML cells by decreasing the expression of BRCA1, CHK1, and RAD51. In this study, we utilized class- and isoform-specific HDACIs and shRNA knockdown of individual HDACs to determine which HDACs are responsible for decreased expression of BRCA1, CHK1, and RAD51 following pan-HDACI treatment in AML cells. We found that inhibition of both HDAC1 and HDAC2 was necessary to decrease the expression of BRCA1, CHK1, and RAD51, enhance cytarabine- or daunorubicin-induced DNA damage and apoptosis, and abrogate cytarabine- or daunorubicin-induced cell cycle checkpoint activation in AML cells. These findings may aid in the development of rationally designed drug combinations for the treatment of AML.

Highlights

The standard treatment for most acute myeloid leukemia (AML) patients, consisting of cytarabine and an anthracycline [e.g., daunorubicin (DNR)], has been used for the past four decades
We found that inhibition of both HDAC1 and HDAC2 was necessary to decrease the expression of BRCA1, CHK1, and RAD51, enhance cytarabine- or daunorubicin-induced DNA damage and apoptosis, and abrogate cytarabine- or daunorubicin-induced cell cycle checkpoint activation in AML cells
We previously demonstrated that panobinostat suppressed the expression of BRCA1, CHK1, and RAD51 which play critical roles in the DNA damage response (DDR), leading to induction of DNA DSBs and apoptosis, and abrogation of the activation of the cell cycle checkpoints induced by ara-C or DNR in AML cells [14]

Summary

INTRODUCTION

The standard treatment for most acute myeloid leukemia (AML) patients, consisting of cytarabine (ara-C) and an anthracycline [e.g., daunorubicin (DNR)], has been used for the past four decades. We previously demonstrated that panobinostat (a pan-HDACI) suppressed the expression of BRCA1, CHK1, and RAD51 which play critical roles in the DNA damage response (DDR), leading to induction of DNA DSBs and apoptosis, and abrogation of the activation of the cell cycle checkpoints induced by ara-C or DNR in AML cells [14]. It is still unknown which HDAC isoforms play a key role in regulating the expression of these proteins.

RESULTS

MATERIALS AND METHODS

CONFLICTS OF INTEREST