TY - JOUR
T1 - Drug-induced inactivation or gene silencing of class I histone deacetylases suppresses ovarian cancer cell growth
T2 - Implications for therapy
AU - Khabele, Dineo
AU - Son, Deok Soo
AU - Parl, Angelika K.
AU - Goldberg, Gary L.
AU - Augenlicht, Leonard H.
AU - Mariadason, John M.
AU - Rice, Valerie Montgomery
N1 - Funding Information:
cancer. Whether the efficacy of FK228 is related to its selectivity against Class I HDAC isoforms is not clear. As current and novel HDAC inhibitors enter the clinic, it will be increasingly important to determine the role of broad‑spectrum versus isoform selective agents in the management of tumors such as ovarian cancer. Finally, the contributory role that we have demonstrated for Class I HDACs in ovarian cancer proliferation, suggests that isoenzyme specific interacting proteins or isoform specific downstream molecular events might also be novel targets of investigation aimed at further improving the treatment options for ovarian cancer. Acknowledgements This research was supported by the Ovarian Cancer Research Fund and in part the Reproductive Scientist Developme.nt Program NIH 5K12HD00849, the Amos Medical Faculty Development Program/Robert Wood Johnson Foundation and the RCMI NIH G2 RR 03032. We thank Dr. William McCulloch (DK), and the Clinical Research Center of Meharry Medical College, grant #P20RR011792 from the National Institutes of Health and RCMI Clinical Research Infrastructure Initiative (DS and VMR); Gloucester Pharmaceuticals (Cambridge, MA) for the romidepsin (FK228); Dr. Andrew Godwin, at Fox Chase Cancer Center (Philadelphia, PA) for the ovarian cell lines; the Vanderbilt Human Tissue Acquisition & Pathology Core Facility (Nashville, TN) for the creation of the tissue array; Melissa Lopez‑Jones and Jiao LTian Dg (IASlbTerRt IEBinUsteTinE College of Medicine) for their technical assistance with the tumor samples; and Drs. Josiah Ochieng, Ifeanyi Arinze, and Lee Limbird (Meharry Medical College) for their helpful comments. References
PY - 2007/5
Y1 - 2007/5
N2 - There is an urgent need to develop new strategies to treat ovarian cancer, the most deadly gynecologic malignancy. Histone deacetylase (HDAC) inhibitors are emerging as novel therapeutic drugs in the treatment of a variety of cancers, including those resistant to standard chemotherapy. Since there are multiple HDAC isoforms, determining the precise role of individual HDAC isoenzymes in the growth and progression of ovarian cancer has the potential to influence the use of selective HDAC inhibitors as strategic therapeutic agents that elicit fewer undesirable side effects. Unfortunately, there is limited information about the expression of HDAC isoforms in human ovarian tissues. This report provides evidence for the first time that Class I HDACs are expressed at significantly higher levels in ovarian cancers in comparison to normal ovarian tissues, with no significant difference in Class II HDAC expression between the two groups. Furthermore, ovarian cancer cells are far more sensitive than normal ovarian cells to the potent HDAC inhibitor romidepsin (FK228), a drug that displays greater inhibitory selectivity for Class I HDACs over Class II isoforms. Using small interfering RNA (siRNA) methodology, we demonstrate that knocking down the gene expression of HDAC3 and other members of the Class I HDAC family suppresses ovarian cancer cell growth. Taken together, the present studies offer several novel findings that have direct relevance for the strategic use of inhibitors that target Class I HDACs, particularly HDAC3, in the treatment of ovarian cancer.
AB - There is an urgent need to develop new strategies to treat ovarian cancer, the most deadly gynecologic malignancy. Histone deacetylase (HDAC) inhibitors are emerging as novel therapeutic drugs in the treatment of a variety of cancers, including those resistant to standard chemotherapy. Since there are multiple HDAC isoforms, determining the precise role of individual HDAC isoenzymes in the growth and progression of ovarian cancer has the potential to influence the use of selective HDAC inhibitors as strategic therapeutic agents that elicit fewer undesirable side effects. Unfortunately, there is limited information about the expression of HDAC isoforms in human ovarian tissues. This report provides evidence for the first time that Class I HDACs are expressed at significantly higher levels in ovarian cancers in comparison to normal ovarian tissues, with no significant difference in Class II HDAC expression between the two groups. Furthermore, ovarian cancer cells are far more sensitive than normal ovarian cells to the potent HDAC inhibitor romidepsin (FK228), a drug that displays greater inhibitory selectivity for Class I HDACs over Class II isoforms. Using small interfering RNA (siRNA) methodology, we demonstrate that knocking down the gene expression of HDAC3 and other members of the Class I HDAC family suppresses ovarian cancer cell growth. Taken together, the present studies offer several novel findings that have direct relevance for the strategic use of inhibitors that target Class I HDACs, particularly HDAC3, in the treatment of ovarian cancer.
KW - Cancer biology
KW - FK228
KW - Histone deacetylases
KW - Molecular therapy
KW - Ovarian cancer
KW - Surgical oncology
KW - siRNA
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UR - http://www.scopus.com/inward/citedby.url?scp=34548226848&partnerID=8YFLogxK
U2 - 10.4161/cbt.6.5.4007
DO - 10.4161/cbt.6.5.4007
M3 - Article
C2 - 17387270
AN - SCOPUS:34548226848
SN - 1538-4047
VL - 6
SP - 795
EP - 801
JO - Cancer Biology and Therapy
JF - Cancer Biology and Therapy
IS - 5
ER -
