1. BRG1 regulates lipid metabolism in hepatocellular carcinoma through the PIK3AP1/PI3K/AKT pathway by mediating GLMP expression
- Author
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Shuang-Jian Qiu, Ruo-Yu Guan, Jian Sun, Cheng Zhou, Jia Fan, Bao-Ye Sun, Gao Liu, Jian Zhou, Zhu-Tao Wang, Pei-Yun Zhou, Zhang-Fu Yang, and Yong Yi
- Subjects
Carcinoma, Hepatocellular ,Phosphatidylinositol 3-Kinases ,03 medical and health sciences ,0302 clinical medicine ,Non-alcoholic Fatty Liver Disease ,Lipid droplet ,Humans ,Medicine ,Protein kinase B ,PI3K/AKT/mTOR pathway ,Adaptor Proteins, Signal Transducing ,Gene knockdown ,Hepatology ,business.industry ,Kinase ,Liver Neoplasms ,Gastroenterology ,Signal transducing adaptor protein ,Lipid metabolism ,Lipid Metabolism ,digestive system diseases ,Cell biology ,030220 oncology & carcinogenesis ,030211 gastroenterology & hepatology ,Phosphatidylinositol 3-Kinase ,business ,Proto-Oncogene Proteins c-akt ,Chromatin immunoprecipitation - Abstract
Background Brahma-related gene 1 (BRG1) is essential for embryogenesis and cellular metabolism. A deficiency of BRG1 in vivo decreases lipid droplets, but the molecular mechanism underlying its role in lipid metabolism associated with hepatocellular carcinoma (HCC) remains unknown. Aims We aimed to determine the role of BRG1 in lipid metabolism in HCC. Methods We assessed the differential expression of BRG1 in HCC and adjacent non-tumorous tissues using tissue microarrays. We stained lipid droplets in HCC cells with Bodipy fluorescence and Oil Red O, and verified BRG1 binding to the promoter region of glycosylated lysosomal membrane protein (GLMP) using chromatin immunoprecipitation. Results The expression of GLMP, a potential lipid metabolism regulator, was suppressed by BRG1 via transcriptional activity. Knockdown of BRG1 decreased lipid droplets, increased GLMP expression and altered the phosphoinositide-3-kinase adaptor protein 1 (PIK3AP1)/phosphatidylinositol-3 kinase (PI3K)/protein kinase B (AKT) pathway in HCC, which further GLMP knockdown partially restored. Thus, GLMP knockdown increased lipid droplets and differentially altered the PI3K/AKT pathway. Conclusions Downregulating BRG1 decreased lipid droplet deposition in HCC cells by upregulating GLMP and altering the PI3K/AKT pathway. Both BRG1 and GLMP might serve as therapeutic targets for disorders associated with dysregulated lipid metabolism, such as NAFLD and NAFLD-associated HCC.
- Published
- 2022