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Assays for Validating Histone Acetyltransferase Inhibitors
Published on: August 6, 2020
HDAC as a therapeutic target for treatment of endometrial cancers
1Cancer Center, First Affiliated Hospital of Xi' an Jiaotong University, Xi'an, Shaanxi Province, China, 710061. renjuan88@aliyun.com.
Abstract:
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.
Insights
Histone deacetylase (HDAC) inhibitors show promise for treating endometrial cancer by reactivating silenced tumor suppressor genes. Studies confirm their potent anti-cancer effects, suggesting a new therapeutic avenue for this malignancy.
Area of Science:
- Oncology
- Epigenetics
- Molecular Biology
Background:
- Epigenetic alterations, including DNA hypermethylation and histone deacetylation, silence tumor suppressor genes, driving cancer development.
- Histone deacetylase (HDAC) inhibitors can reverse gene silencing, halt cell proliferation, and induce apoptosis in cancer cells.
- Endometrial cancer (EC) exhibits significant epigenetic dysregulation, including HDAC overexpression and silencing of key genes like MLH1 and PTEN, indicating potential sensitivity to HDAC inhibitors.
Purpose of the Study:
- To review the efficacy of HDAC inhibitors as a therapeutic strategy for endometrial cancer.
- To summarize current research on HDAC inhibitors' anti-cancer effects in various models of EC.
- To provide an update on novel HDAC inhibitors and their potential combination therapies for EC.
Main Methods:
- In vitro studies using cancer cell cultures.
- In vivo experiments utilizing mouse xenograft models.
- Review of existing clinical trial data and preclinical research findings.
Main Results:
- HDAC inhibitors demonstrate potent anti-cancer effects by reactivating silenced genes, inhibiting cell cycle progression, and inducing apoptosis.
- Preclinical studies consistently show promising results for HDAC inhibitors in endometrial cancer models.
- SAHA (Vorinostat), an HDAC inhibitor, is approved for lymphoma treatment, supporting the therapeutic potential of this drug class.
Conclusions:
- HDAC inhibitors represent a promising class of chemotherapeutic agents for endometrial cancer due to the specific epigenetic landscape of this malignancy.
- Further research and clinical trials are warranted to explore the full potential of novel HDAC inhibitors and combination therapies for EC treatment.
- The review highlights the need for continued investigation into HDAC inhibitors, including their combination with radiation and conventional therapies, for enhanced endometrial cancer treatment outcomes.
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