Inhibition of Histone Deacetylase 3 Causes Replication Stress in Cutaneous T Cell Lymphoma

Christina E. Wells, Srividya Bhaskara, Kristy R. Stengel, Yue Zhao, Bianca Sirbu, Benjamin Chagot, David Cortez, Dineo Khabele, Walter J. Chazin, Andrew Cooper, Vincent Jacques, James Rusche, Christine M. Eischen, Laura Y. McGirt, Scott W. Hiebert

Research output: Contribution to journalArticlepeer-review

68 Scopus citations

Abstract

Given the fundamental roles of histone deacetylases (HDACs) in the regulation of DNA repair, replication, transcription and chromatin structure, it is fitting that therapies targeting HDAC activities are now being explored as anti-cancer agents. In fact, two histone deacetylase inhibitors (HDIs), SAHA and Depsipeptide, are FDA approved for single-agent treatment of refractory cutaneous T cell lymphoma (CTCL). An important target of these HDIs, histone deacetylase 3 (HDAC3), regulates processes such as DNA repair, metabolism, and tumorigenesis through the regulation of chromatin structure and gene expression. Here we show that HDAC3 inhibition using a first in class selective inhibitor, RGFP966, resulted in decreased cell growth in CTCL cell lines due to increased apoptosis that was associated with DNA damage and impaired S phase progression. Through isolation of proteins on nascent DNA (iPOND), we found that HDAC3 was associated with chromatin and is present at and around DNA replication forks. DNA fiber labeling analysis showed that inhibition of HDAC3 resulted in a significant reduction in DNA replication fork velocity within the first hour of drug treatment. These results suggest that selective inhibition of HDAC3 could be useful in treatment of CTCL by disrupting DNA replication of the rapidly cycling tumor cells, ultimately leading to cell death.

Original languageEnglish (US)
Article numbere68915
JournalPloS one
Volume8
Issue number7
DOIs
StatePublished - Jul 22 2013
Externally publishedYes

ASJC Scopus subject areas

  • General

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