Valproic acid targets HDAC1/2 and HDAC1/PTEN/Akt signalling to inhibit cell proliferation via the induction of autophagy in gastric cancer

• Published in: The FEBS journal 2020-05, Vol.287 (10), p.2118-2133
• Main Authors: Sun, Jie, Piao, Junjie, Li, Nan, Yang, Yang, Kim, Ki‐Yeol, Lin, Zhenhua
• Format: Article
• Language: English
• Subjects: AKT protein; Animals; Anticancer properties; Anticonvulsants; antitumour agent; Apoptosis; Apoptosis - drug effects; Autophagy; Autophagy - drug effects; Beclin-1 - genetics; Biomarkers; Cancer; Cell differentiation; Cell Line, Tumor; Cell proliferation; Cell Proliferation - drug effects; Chemical compounds; Fatty acids; Gastric cancer; Gene Expression Regulation, Neoplastic - drug effects; HDAC; HDAC1/PTEN/Akt; Heterografts; Histone deacetylase; Histone Deacetylase 1 - genetics; Histone Deacetylase 2 - genetics; Histone Deacetylase Inhibitors; Humans; Mice; Oncogene Protein v-akt - genetics; Phagocytosis; Pharmacology; Proto-Oncogene Proteins c-bcl-2 - genetics; PTEN Phosphohydrolase - genetics; PTEN protein; Seizures; Signal transduction; Signal Transduction - drug effects; Signaling; Stomach Neoplasms - drug therapy; Stomach Neoplasms - genetics; Stomach Neoplasms - pathology; Valproic acid; Valproic Acid - pharmacology; VPA; Xenografts; Xenotransplantation
• ISSN: 1742-464X; 1742-4658
• DOI: 10.1111/febs.15122

Valproic acid (2‐propylpentanoic acid, VPA) has been widely used as an anticonvulsant drug and is a choice drug for seizure treatment. VPA is also used as a short‐chain fatty acid HDAC inhibitor that affects proliferation and differentiation and induces cell apoptosis in both solid and haematologic malignancies. Here, we observed that VPA treatment inhibited HDAC1/2 activity and induced autophagy in gastric cancer cells, leading to apoptosis. VPA‐induced apoptosis occurred through inhibition of the HDAC1/PTEN/Akt signalling pathway and involved alterations in Bcl‐2 and Beclin‐1. The antitumour effects of VPA were verified in vivo using SGC‐7901 xenograft models. Moreover, we evaluated the expression of HDAC1/2 in gastric cancer patient samples and revealed a positive correlation between HDAC1/2 overexpression and poor prognosis. These findings indicate that VPA may serve as a potential therapeutic agent for gastric cancer and that HDAC1/2 might be a promising therapeutic biomarker for the disease. Valproic acid (VPA) is used as a short‐chain fatty acid HDAC inhibitor. We demonstrated that VPA inhibited HDAC1/2 activity and induced autophagy in gastric cancer though HDAC1/PTEN/Akt pathway inactivation. Moreover, we revealed a positive correlation between HDAC1/2 overexpression and poor prognosis in gastric cancer patients. These results suggest that VPA might be a potential agent for gastric cancer treatment and that HDAC1/2 may serve as a therapeutic target for gastric cancer.