HDAC as a therapeutic target for treatment of endometrial cancers

• Published in: Current pharmaceutical design Vol. 20; no. 11; p. 1847
• Main Authors: Ren, Juan, Zhang, Jia, Cai, Hui, Li, Yi, Zhang, Yuelang, Zhang, Xiaozhi, Zhao, Dongli, Li, Zongfang, Ma, Hongbing, Wang, Jiansheng, Gao, Yan-E, Xiao, Lisha, Liu, Rui, Qian, Jiansheng, Liu, Yan, Wei, Hongxia, Li, Jinping
• Format: Journal Article
• Language: English
• Published: United Arab Emirates 01.04.2014
• Subjects: Animals; Antineoplastic Agents - pharmacology; Apoptosis - drug effects; DNA Methylation; Endometrial Neoplasms - drug therapy; Endometrial Neoplasms - genetics; Endometrial Neoplasms - pathology; Epigenesis, Genetic; Female; Gene Expression Regulation, Neoplastic - drug effects; Gene Silencing; Histone Deacetylase Inhibitors - pharmacology; Humans; Hydroxamic Acids - pharmacology; Mice; Molecular Targeted Therapy; Vorinostat
• ISSN: 1873-4286
• DOI: 10.2174/13816128113199990528

Accumulating evidence suggested that epigenetic changes such as promoter-specific DNA hypermethylation and histone deacetylation cause tumor suppressor gene silencing and contribute to malignant transformation. Treatment of cancer cells with HDAC inhibitors can reactivate the expression of silenced genes, block the cell cycle, and induce cell apoptosis. In vitro experiments in cancer cell cultures and in vivo studies using mouse xynograft model have shown that HDAC inhibitors deliver potent anti-cancer effects. Clinical trials have led to approval of SAHA (Vorinostat) for treatment of lymphoma. Endometrial cancer (EC) is the most frequent malignancy in women's reproductive tract. EC is known for extensive epigenetic alterations, including overexpression of HDAC and DNMT enzymes, and the frequent epigenetic silencing of DNA repair genes such as MLH1, tumor suppressor genes PTEN, and progesterone receptor, which suggests a potentially high sensitivity of this type of cancer to HDAC inhibitors. Indeed, studies from many laboratories using various models have shown that HDAC inhibitors are promising chemotherapy reagents for endometrial cancers. This review summarizes the results from these studies, with an emphasis to provide an update on the new findings from new drugs. Background information on HDAC expression in EC, and features of HDAC inhibitors are presented based on their relevance to our focused topic. The combined application of HDAC inhibitors with radiation therapy and other conventional therapeutic reagents are also discussed.