Silencing MYH9 blocks HBx-induced GSK3β ubiquitination and degradation to inhibit tumor stemness in hepatocellular carcinoma
Authors: Zhan Liu
Rong-Cheng Luo
Ai-Min Li
Yong-Hao Li
Shi Zuo
Wei-Yi Fang
Xian Lin
Yi-Yi Liu
Ying-Ying Xie
Zhen Liu
Chen Liu
Yu-Jiao Zou
Journal: Signal Transduction and Targeted Therapy (2020)
Discipline: MOLECULAR BIOLOGY & GENETICS
Keywords: MYH9; tumor stemness; hepatocellular carcinoma; GSK3β; ubiquitin-mediated degradation
Affiliations: Cancer Center, Integrated Hospital of Traditional Chinese Medicine, Southern Medical University, Guangzhou, Guangdong, People's Republic of China, 510310., Department of Hepatobiliary Surgery, Affiliated Hospital of Guizhou Medical University, Guiyang, Guizhou, People's Republic of China, 550004., Department of Gastroenterology and Clinical Nutrition, The First Affiliated Hospital (People's Hospital of Hunan Province), Hunan Normal University, Changsha, Hunan, People's Republic of China, 410002., Cancer Center, Integrated Hospital of Traditional Chinese Medicine, Southern Medical University, Guangzhou, Guangdong, People's Republic of China, 510310. ., Guangzhou Municipal and Guangdong Provincial Key Laboratory of Protein Modification and Degradation, State Key Laboratory of Respiratory Disease, School of Basic Medical Sciences, Guangzhou Medical University, Affiliated Cancer Hospital & Institute of Guangzhou Medical University, Guangzhou, Guangdong, People's Republic of China, 510095. ., Cancer Institute, School of Basic Medical Science, Southern Medical University, Guangzhou, Guangdong, People's Republic of China, 510515. .

Abstract:  MYH9 has dual functions in tumors. However, its role in inducing tumor stemness in hepatocellular carcinoma (HCC) is not yet determined. Here, we found that MYH9 is an effective promoter of tumor stemness that facilitates hepatocellular carcinoma pathogenesis. Importantly, targeting MYH9 remarkably improved the survival of hepatocellular carcinoma-bearing mice and promoted sorafenib sensitivity of hepatocellular carcinoma cells in vivo. Mechanistic analysis suggested that MYH9 interacted with GSK3β and reduced its protein expression by ubiquitin-mediated degradation, which therefore dysregulated the β-catenin destruction complex and induced the downstream tumor stemness phenotype, epithelial-mesenchymal transition, and c-Jun signaling in HCC. C-Jun transcriptionally stimulated MYH9 expression and formed an MYH9/GSK3β/β-catenin/c-Jun feedback loop. X protein is a hepatitis B virus (HBV)-encoded key oncogenic protein that promotes HCC pathogenesis. Interestingly, we observed that HBV X protein (HBX) interacted with MYH9 and induced its expression by modulating GSK3β/β-catenin/c-Jun signaling. Targeting MYH9 blocked HBX-induced GSK3β ubiquitination to activate the β-catenin destruction complex and suppressed cancer stemness and EMT. Based on TCGA database analysis, MYH9 was found to be elevated and conferred poor prognosis for hepatocellular carcinoma patients. In clinical samples, high MYH9 expression levels predicted poor prognosis of hepatocellular carcinoma patients. These findings identify the suppression of MYH9 as an alternative approach for the effective eradication of CSC properties to inhibit cancer migration, invasion, growth, and sorafenib resistance in HCC patients. Our study demonstrated that MYH9 is a crucial therapeutic target in HCC. 

Retracted: No

PubPeer comments:
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