Association of changes in expression of HDAC and SIRT genes after drug treatment with cancer cell line sensitivity to kinase inhibitors

Author:

Krushkal, Julia [ORCID]

Zhao, Yingdong [ORCID]

Roney, Kyle

Zhu, Weimin

Brooks,Alan

Wilsker,Deborah

Parchment, Ralph E

McShane, Lisa M [ORCID]

Doroshow, James H
Author Address

Biometric Research Program, Division of Cancer Treatment and Diagnosis, National Cancer Institute, Rockville, MD, USA., Department of Biostatistics and Bioinformatics, George Washington University, Washington, DC, USA., Clinical Pharmacodynamic Biomarkers Program, Applied/Developmental Research Directorate, Frederick National Laboratory for Cancer Research, Frederick, MD, USA., Division of Cancer Treatment and Diagnosis and Center for Cancer Research, National Cancer Institute, Bethesda, MD, USA.,

Abstract:

Histone deacetylases (HDACs) and sirtuins (SIRTs) are important epigenetic regulators of cancer pathways. There is a limited understanding of how transcriptional regulation of their genes is affected by chemotherapeutic agents, and how such transcriptional changes affect tumour sensitivity to drug treatment. We investigated the concerted transcriptional response of HDAC and SIRT genes to 15 approved antitumor agents in the NCI-60 cancer cell line panel. Antitumor agents with diverse mechanisms of action induced upregulation or downregulation of multiple HDAC and SIRT genes. HDAC5 was upregulated by dasatinib and erlotinib in the majority of the cell lines. Tumour cell line sensitivity to kinase inhibitors was associated with upregulation of HDAC5, HDAC1, and several SIRT genes. We confirmed changes in HDAC and SIRT expression in independent datasets. We also experimentally validated the upregulation of HDAC5 mRNA and protein expression by dasatinib in the highly sensitive IGROV1 cell line. HDAC5 was not upregulated in the UACC-257 cell line resistant to dasatinib. The effects of cancer drug treatment on expression of HDAC and SIRT genes may influence chemosensitivity and may need to be considered during chemotherapy.

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