Identification of HDAC9 as a viable therapeutic target for the treatment of gastric cancer
| Autor: | Shigang Ding, Kai Xiong, Yang Du, Jie Tian, Hejun Zhang |
|---|---|
| Jazyk: | angličtina |
| Rok vydání: | 2019 |
| Předmět: |
Male
Clinical Biochemistry Mice Nude lcsh:Medicine Antineoplastic Agents Apoptosis Adenocarcinoma Biochemistry Article Gene Expression Regulation Enzymologic Histone Deacetylases lcsh:Biochemistry Prognostic markers Mice Stomach Neoplasms In vivo medicine Animals Humans lcsh:QD415-436 Molecular Targeted Therapy Stomach cancer Molecular Biology Cells Cultured Cell Proliferation Cisplatin Mice Inbred BALB C Vorinostat Cell growth business.industry HDAC9 lcsh:R Cancer Cell Cycle Checkpoints medicine.disease Xenograft Model Antitumor Assays Gene Expression Regulation Neoplastic Histone Deacetylase Inhibitors Repressor Proteins Treatment Outcome Cancer cell Cancer research Molecular Medicine Cancer imaging Histone deacetylase business medicine.drug |
| Zdroj: | Experimental and Molecular Medicine, Vol 51, Iss 8, Pp 1-15 (2019) Experimental & Molecular Medicine |
| ISSN: | 2092-6413 1226-3613 |
| Popis: | Histone deacetylase inhibitors (HDACis) are a new class of anticancer drugs confirmed to have good therapeutic effects against gastric cancer (GC) in preclinical experiments, but most HDACis are non-selective (pan-HDACis), with highly toxic side effects. Therefore, it is necessary to screen HDAC family members that play key roles in GC as therapeutic targets to reduce toxic side effects. In this study, we evaluated the targeting specificity of the HDACi suberoylanilide hydroxamic acid (SAHA) for GC via fluorescence molecular imaging (FMI). In vitro FMI results showed that SAHA had higher binding affinity for GC cells than for normal gastric cells. In vivo FMI of gastric tumor-bearing mice confirmed that SAHA can be enriched in GC tissues. However, there was also a high-concentration distribution in normal organs such as the stomach and lungs, suggesting potential side effects. In addition, we found that among the HDAC family members, HDAC9 was the most significantly upregulated in GC cells, and we verified this upregulation in GC tissues. Further experiments confirmed that knockdown of HDAC9 inhibits cell growth, reduces colony formation, and induces apoptosis and cell cycle arrest. These results suggest that HDAC9 has an oncogenic role in GC. Moreover, HDAC9 siRNA suppressed GC tumor growth and enhanced the antitumor efficacy of cisplatin in GC treatment by inhibiting the proliferation and inducing the apoptosis of GC cells in vitro and in vivo. Our findings suggest that the development of HDAC9-selective HDACis is a potential approach to improve the efficacy of chemotherapy and reduce systemic toxicity. Stomach cancer: identifying the right target Inhibiting histone deacetylase 9 (HDAC9), a protein that regulates gene expression, reduces stomach cancer cell growth. The efficacy of current treatments for stomach cancer is limited. Although HDACs have emerged as promising therapeutic targets, non-selective HDAC inhibitors can cause severe side effects. Shigang Ding at Peking University Third Hospital in Beijing, China, and colleagues found that human stomach cancer cells have significantly higher levels of HDAC9 than other members of the HDAC family and that high HDAC9 levels are associated with reduced patient survival. Interfering with the production of HDAC9 protein improved the efficacy of the chemotherapeutic drug cisplatin in mice with stomach cancer. The authors suggest that selective HDAC9 inhibitors could help to improve the survival of patients with this type of cancer. |
| Databáze: | OpenAIRE |
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