Journal
PLOS ONE
Volume 8, Issue 7, Pages -Publisher
PUBLIC LIBRARY SCIENCE
DOI: 10.1371/journal.pone.0068915
Keywords
-
Categories
Funding
- T. J. Martell Foundation
- Robert J. Kleberg, Jr. and Helen C. Kleberg Foundation
- National Institutes of Health [R01-CA64140, RO1-CA164605, RO1-CA109355]
- Vanderbilt Digestive Disease Research grant [P30DK058404]
- Vanderbilt-Ingram Cancer Center support grant [NCI P30CA68485]
- National Cancer Institute [1F32CA138091]
- Dermatology Foundation
- NIH (Vanderbilt Clinical Oncology) [5K12CA090625]
- NATIONAL CANCER INSTITUTE [K12CA090625, K08CA148887, F32CA138091, T32CA009582, R01CA148950, R01CA141071, P30CA068485, R01CA109355, R01CA164605, R01CA136933, R01CA064140] Funding Source: NIH RePORTER
- NATIONAL INSTITUTE OF DIABETES AND DIGESTIVE AND KIDNEY DISEASES [P30DK058404] Funding Source: NIH RePORTER
- NATIONAL INSTITUTE OF ENVIRONMENTAL HEALTH SCIENCES [T32ES007028, P30ES000267] Funding Source: NIH RePORTER
Ask authors/readers for more resources
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.
Authors
I am an author on this paper
Click your name to claim this paper and add it to your profile.
Reviews
Recommended
No Data Available