Research Papers:

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

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

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Oncotarget. 2017; 8:6319-6329. https://doi.org/10.18632/oncotarget.14062

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Jianyun Zhao1,4,5,*, Chengzhi Xie2,3,*, Holly Edwards2,3, Guan Wang1, Jeffrey W. Taub3,4,5, Yubin Ge1,2,3,4

1National Engineering Laboratory for AIDS Vaccine and Key Laboratory for Molecular Enzymology and Engineering, The Ministry of Education, School of Life Sciences, Jilin University, Changchun, P. R. China

2Department of Oncology, Wayne State University School of Medicine, Detroit, MI, USA

3Molecular Therapeutics Program, Barbara Ann Karmanos Cancer Institute, Wayne State University School of Medicine, Detroit, MI, USA

4Department of Pediatrics, Wayne State University School of Medicine, Detroit, MI, USA

5Division of Pediatric Hematology/Oncology, Children’s Hospital of Michigan, Detroit, MI, USA

*These authors are contributed equally to this work

Correspondence to:

Yubin Ge, email: [email protected]

Jeffrey W. Taub, email: [email protected]

Keywords: HDAC, BRCA1, CHK1, RAD51, acute myeloid leukemia

Received: October 19, 2016     Accepted: December 13, 2016     Published: December 21, 2016


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.

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