RGS19 activates the MYH9/β-catenin/c-Myc positive feedback loop in hepatocellular carcinoma

• Published in: Experimental & molecular medicine Vol. 56; no. 6; pp. 1412 - 1425
• Main Authors: Ke, Shanjia, Lu, Shounan, Xu, Yanan, Bai, Miaoyu, Yu, Hongjun, Yin, Bing, Wang, Chaoqun, Feng, Zhigang, Li, Zihao, Huang, Jingjing, Li, Xinglong, Qian, Baolin, Hua, Yongliang, Fu, Yao, Sun, Bei, Wu, Yaohua, Ma, Yong
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 01.06.2024; Springer Nature B.V; Nature Publishing Group
• Subjects: 13/109; 13/51; 14/19; 38/89; 45/15; 45/70; 45/77; 631/337/458/582; 631/67/395; 64/60; 82/58; 82/83; Animal models; Animals; Artificial intelligence; beta Catenin - metabolism; Biomedical and Life Sciences; Biomedicine; c-Myc protein; Carcinoma, Hepatocellular - genetics; Carcinoma, Hepatocellular - metabolism; Carcinoma, Hepatocellular - pathology; Cell culture; Cell Line, Tumor; Cell Proliferation; Feedback; Feedback, Physiological; Female; Gene expression; Gene Expression Regulation, Neoplastic; Hepatocellular carcinoma; Humans; Liver cancer; Liver Neoplasms - genetics; Liver Neoplasms - metabolism; Liver Neoplasms - pathology; Male; Medical Biochemistry; Medical prognosis; Metastases; Mice; Molecular Medicine; Myc protein; Myosin Heavy Chains - genetics; Myosin Heavy Chains - metabolism; Patients; Prognosis; Proteins; Proto-Oncogene Proteins c-myc - genetics; Proto-Oncogene Proteins c-myc - metabolism; RGS Proteins - genetics; RGS Proteins - metabolism; Signal Transduction; Stem Cells; Ubiquitin-protein ligase; β-Catenin
• ISSN: 2092-6413; 1226-3613; 2092-6413
• DOI: 10.1038/s12276-024-01244-9

Hepatocellular carcinoma (HCC) is one of the most common fatal cancers worldwide, and the identification of novel treatment targets and prognostic biomarkers is urgently needed because of its unsatisfactory prognosis. Regulator of G-protein signaling 19 (RGS19) is a multifunctional protein that regulates the progression of various cancers. However, the specific function of RGS19 in HCC remains unclear. The expression of RGS19 was determined in clinical HCC samples. Functional and molecular biology experiments involving RGS19 were performed to explore the potential mechanisms of RGS19 in HCC. The results showed that the expression of RGS19 is upregulated in HCC tissues and is significantly associated with poor prognosis in HCC patients. RGS19 promotes the proliferation and metastasis of HCC cells in vitro and in vivo. Mechanistically, RGS19, via its RGS domain, stabilizes the MYH9 protein by directly inhibiting the interaction of MYH9 with STUB1, which has been identified as an E3 ligase of MYH9. Moreover, RGS19 activates β-catenin/c-Myc signaling via MYH9, and RGS19 is also a transcriptional target gene of c-Myc. A positive feedback loop formed by RGS19, MYH9, and the β-catenin/c-Myc axis was found in HCC. In conclusion, our research revealed that competition between RGS19 and STUB1 is a critical mechanism of MYH9 regulation and that the RGS19/MYH9/β-catenin/c-Myc feedback loop may represent a promising strategy for HCC therapy. RGS19 in HCC: Key Player in Poor Prognosis Mechanisms Liver cancer is a worldwide health issue, with a type called hepatocellular carcinoma making up over 90% of cases. Researchers aimed to understand the biological workings of HCC to better predict patient outcomes. They studied the regulator of G protein signaling family, RGS19, a protein linked to several cancers’ progression. The study involved 100 HCC patients and used methods like gene expression analysis, cell culture experiments, and animal models. They found that RGS19 is overproduced in HCC tissues and high production is linked to poor survival rates. They also found RGS19 encourages growth and spread of HCC cells by interacting with another protein, MYH9, and activating cancer-related signaling pathway. The findings suggest that RGS19 could be a potential diagnostic marker and treatment target for HCC. The study also emphasizes the need for more research on RGS proteins’ role in cancer. This summary was initially drafted using artificial intelligence, then revised and fact-checked by the author.