Silencing MYH9 blocks HBx-induced GSK3β ubiquitination and degradation to inhibit tumor stemness in hepatocellular carcinoma.

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.

• Authors: Xian Lin, Ai-Min Li, Yong-Hao Li, Rong-Cheng Luo, Yu-Jiao Zou, Yi-Yi Liu, Chen Liu, Ying-Ying Xie, Shi Zuo, Zhan Liu, Zhen Liu, Wei-Yi Fang
• Journal: Signal transduction and targeted therapy (Signal Transduct Target Ther) Vol. 5 Issue 1 Pg. 13 (02 14 2020) ISSN: 2059-3635 [Electronic] England
• PMID: 32296025 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• CTNNB1 protein, human
• MYH9 protein, human
• Trans-Activators
• Viral Regulatory and Accessory Proteins
• beta Catenin
• hepatitis B virus X protein
• Sorafenib
• GSK3B protein, human
• Glycogen Synthase Kinase 3 beta
• JNK Mitogen-Activated Protein Kinases
• Myosin Heavy Chains

Topics

• Animals
• Carcinoma, Hepatocellular (drug therapy, genetics, pathology)
• Cell Line, Tumor
• Cell Movement (drug effects)
• Epithelial-Mesenchymal Transition (genetics)
• Gene Expression Regulation, Neoplastic (drug effects)
• Gene Silencing (drug effects)
• Glycogen Synthase Kinase 3 beta (genetics)
• Heterografts
• Humans
• JNK Mitogen-Activated Protein Kinases (genetics)
• Liver Neoplasms (drug therapy, genetics, pathology)
• Mice
• Myosin Heavy Chains (genetics)
• Neoplastic Stem Cells (drug effects)
• Sorafenib (pharmacology)
• Trans-Activators (genetics)
• Ubiquitination (drug effects)
• Viral Regulatory and Accessory Proteins (genetics)
• Wnt Signaling Pathway (drug effects)
• beta Catenin (genetics)