BCL11B suppresses tumor progression and stem cell traits in hepatocellular carcinoma by restoring p53 signaling activity

• Published in: Cell death & disease 2020-10, Vol.11 (10), p.895, Article 895
• Main Authors: Yang, Wen-Jing, Sun, Yun-Fan, Jin, An-Li, Lv, Li-Hua, Zhu, Jie, Wang, Bei-Li, Zhou, Yan, Zhang, Chun-Yan, Wang, Hao, Hu, Bo, Wang, Peng-Xiang, Te, Liu, Pan, Bai-Shen, Zhou, Jian, Fan, Jia, Yang, Xin-Rong, Guo, Wei
• Format: Article
• Language: English
• Subjects: 13; 13/100; 13/106; 13/109; 13/2; 13/31; 13/51; 13/89; 13/95; 14/34; 42/100; 631/67/1504/1610; 631/67/71; 631/80/83; 82/47; Animals; Antibodies; Antineoplastic Agents - pharmacology; Apoptosis; Apoptosis - drug effects; Biochemistry; Biomedical and Life Sciences; Carcinogenesis - drug effects; Carcinogenesis - genetics; Carcinogenesis - metabolism; Carcinoma, Hepatocellular - pathology; Cell Biology; Cell Culture; Cell cycle; Cell Cycle - drug effects; Cell differentiation; Cell Line, Tumor; Cell Movement - drug effects; Cell Proliferation - drug effects; Cell self-renewal; Drug resistance; Drug Synergism; Ectopic expression; Gene Expression Regulation, Neoplastic; Genes, Tumor Suppressor; Hep G2 Cells; Hepatocellular carcinoma; Hepatocytes; Humans; Immunology; Life Sciences; Liver cancer; Liver Neoplasms - pathology; Lymphoma; Male; Metastases; Mice; Mice, Nude; Neoplastic Stem Cells - drug effects; p53 Protein; Repressor Proteins - pharmacology; Repressor Proteins - physiology; Signal Transduction; Stem cells; Transcription; Tumor Protein p73 - physiology; Tumor suppressor genes; Tumor Suppressor Protein p53 - genetics; Tumor Suppressor Protein p53 - physiology; Tumor Suppressor Proteins - pharmacology; Tumor Suppressor Proteins - physiology; Tumorigenesis; Xenograft Model Antitumor Assays
• ISSN: 2041-4889; 2041-4889
• DOI: 10.1038/s41419-020-03115-3

Accumulating evidence indicates that hepatocellular carcinoma (HCC) tumorigenesis, recurrence, metastasis, and therapeutic resistance are strongly associated with liver cancer stem cells (CSCs), a rare subpopulation of highly tumorigenic cells with self-renewal capacity and differentiation potential. Previous studies identified B cell leukemia/lymphoma-11b (BCL11B) as a novel tumor suppressor with impressive capacity to restrain CSC traits. However, the implications of BCL11B in HCC remain unclear. In this study, we found that low BCL11B expression was an independent indicator for shorter overall survival (OS) and time to recurrence (TTR) for HCC patients with surgical resection. In vitro and in vivo experiments confirmed BCL11B as a tumor suppressor in HCC with inhibitory effects on proliferation, cell cycle progression, apoptosis, and mobility. Furthermore, BCL11B could suppress CSC traits, as evidenced by dramatically decreased tumor spheroid formation, self-renewal potential and drug resistance. A Cignal Finder Array and dual-luciferase activity reporter assays revealed that BCL11B could activate the transcription of P73 via an E2F1-dependent manner. Thus, we concluded that BCL11B is a strong suppressor of retaining CSC traits in HCC. Ectopic expression of BCL11B might be a promising strategy for anti-HCC treatment with the potential to cure HBV-related HCC regardless of P53 mutation status.