Lysine-specific demethylase 1 promotes the stemness and chemoresistance of Lgr5+ liver cancer initiating cells by suppressing negative regulators of β-catenin signaling

• Published in: Oncogene Vol. 34; no. 24; pp. 3188 - 3198
• Main Authors: Lei, Z-J, Wang, J, Xiao, H-L, Guo, Y, Wang, T, Li, Q, Liu, L, Luo, X, Fan, L-L, Lin, L, Mao, C-Y, Wang, S-N, Wei, Y-L, Lan, C-H, Jiang, J, Yang, X-J, Liu, P-D, Chen, D-F, Wang, B
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 11.06.2015; Nature Publishing Group
• Subjects: 13/100; 38/1; 38/89; 631/67/71; 82/80; 96/1; 96/109; 96/95; Adenomatous polyposis coli; Animals; Apoptosis; beta Catenin - metabolism; Carcinoma, Hepatocellular - genetics; Carcinoma, Hepatocellular - pathology; Cell Biology; Cell differentiation; Cell self-renewal; Chemoresistance; Chemotherapy; Demethylation; DNA methylation; Down-Regulation; Drug resistance; Drug Resistance, Neoplasm - genetics; G protein-coupled receptors; Gene Expression Regulation, Neoplastic; Hepatocellular carcinoma; Hepatocytes; Histone Demethylases - genetics; Histone Demethylases - physiology; Histone H3; Human Genetics; Humans; Internal Medicine; Leucine; Liver cancer; Liver Neoplasms - genetics; Liver Neoplasms - pathology; Lysine; Male; Medicine; Medicine & Public Health; Mice; Mice, Nude; Neoplastic Stem Cells - metabolism; Neoplastic Stem Cells - pathology; Oncology; original-article; Receptors, G-Protein-Coupled - metabolism; Stem cells; Transcription activation; Tumor Cells, Cultured; Tumors; Wnt Signaling Pathway - genetics; β-Catenin
• ISSN: 0950-9232; 1476-5594
• DOI: 10.1038/onc.2015.129

Cancer initiating cells (CICs) are responsible for the unrestrained cell growth and chemoresistance of malignant tumors. Histone demethylation has been shown to be crucial for self-renewal/differentiation of stem cells, but it remains elusive whether lysine-specific demethylase 1 (LSD1) regulates the stemness properties of CICs. Here we report that the abundant expression of leucine-rich repeat-containing G-protein-coupled receptor 5 (Lgr5) is associated with the progression of hepatocellular carcinoma (HCC). Lgr5 + HCC cells behave similarly to CICs and are highly tumorigenic and resistant to chemotherapeutic agents. Importantly, Lgr5 + cells express higher levels of LSD1, which in turn regulates Lgr5 expression and promotes the self-renewal and drug resistance of Lgr5 + CICs. Mechanistically, LSD1 promotes β-catenin activation by inhibiting the expression of several suppressors of β-catenin signaling, especially Prickle1 and APC in Lgr5 + CICs, by directly regulating the levels of mono- and di-methylation of histone H3 lysine-4 at the promoters of these genes. Furthermore, LSD1-associated activation of the β-catenin signaling is essential for maintaining the activity of Lgr5 + CICs. Together, our findings unravel the LSD1/Prickle1/APC/β-catenin signaling axis as a novel molecular circuit regulating the stemness and chemoresistance of hepatic Lgr5 + CICs and provide potential targets to improve chemotherapeutic efficacies against HCC.