TY - JOUR
T1 - Inhibition of Histone Deacetylase 3 Causes Replication Stress in Cutaneous T Cell Lymphoma
AU - Wells, Christina E.
AU - Bhaskara, Srividya
AU - Stengel, Kristy R.
AU - Zhao, Yue
AU - Sirbu, Bianca
AU - Chagot, Benjamin
AU - Cortez, David
AU - Khabele, Dineo
AU - Chazin, Walter J.
AU - Cooper, Andrew
AU - Jacques, Vincent
AU - Rusche, James
AU - Eischen, Christine M.
AU - McGirt, Laura Y.
AU - Hiebert, Scott W.
PY - 2013/7/22
Y1 - 2013/7/22
N2 - 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.
AB - 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.
UR - http://www.scopus.com/inward/record.url?scp=84880655164&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=84880655164&partnerID=8YFLogxK
U2 - 10.1371/journal.pone.0068915
DO - 10.1371/journal.pone.0068915
M3 - Article
C2 - 23894374
AN - SCOPUS:84880655164
SN - 1932-6203
VL - 8
JO - PloS one
JF - PloS one
IS - 7
M1 - e68915
ER -