title: Lysine-specific demethylase 1 promotes the stemness and chemoresistance of Lgr5(+) liver cancer initiating cells by suppressing negative regulators of β-catenin signaling.
abstract: 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.
authors.affiliation: Department of Gastroenterology, Institute of Surgery Research, Daping Hospital, Third Military Medical University, Chongqing, China.
authors.forename: Z-J
authors.initials: ZJ
authors.lastname: Lei
authors.affiliation: Department of Gastroenterology, Institute of Surgery Research, Daping Hospital, Third Military Medical University, Chongqing, China.
authors.forename: J
authors.initials: J
authors.lastname: Wang
authors.affiliation: Department of Pathology, Institute of Surgery Research, Daping Hospital, Third Military Medical University, Chongqing, China.
authors.forename: H-L
authors.initials: HL
authors.lastname: Xiao
authors.affiliation: Department of Gastroenterology, Institute of Surgery Research, Daping Hospital, Third Military Medical University, Chongqing, China.
authors.forename: Y
authors.initials: Y
authors.lastname: Guo
authors.affiliation: Department of Gastroenterology, Institute of Surgery Research, Daping Hospital, Third Military Medical University, Chongqing, China.
authors.forename: T
authors.initials: T
authors.lastname: Wang
authors.affiliation: Department of Gastroenterology, Institute of Surgery Research, Daping Hospital, Third Military Medical University, Chongqing, China.
authors.forename: Q
authors.initials: Q
authors.lastname: Li
authors.affiliation: Department of Gastroenterology, Institute of Surgery Research, Daping Hospital, Third Military Medical University, Chongqing, China.
authors.forename: L
authors.initials: L
authors.lastname: Liu
authors.affiliation: Department of Gastroenterology, Institute of Surgery Research, Daping Hospital, Third Military Medical University, Chongqing, China.
authors.forename: X
authors.initials: X
authors.lastname: Luo
authors.affiliation: Department of Gastroenterology, Institute of Surgery Research, Daping Hospital, Third Military Medical University, Chongqing, China.
authors.forename: L-L
authors.initials: LL
authors.lastname: Fan
authors.affiliation: Department of Pathology, Institute of Surgery Research, Daping Hospital, Third Military Medical University, Chongqing, China.
authors.forename: L
authors.initials: L
authors.lastname: Lin
authors.affiliation: Department of Pathology, Institute of Surgery Research, Daping Hospital, Third Military Medical University, Chongqing, China.
authors.forename: C-Y
authors.initials: CY
authors.lastname: Mao
authors.affiliation: Department of Radiology, Institute of Surgery Research, Daping Hospital, Third Military Medical University, Chongqing, China.
authors.forename: S-N
authors.initials: SN
authors.lastname: Wang
authors.affiliation: Department of Gastroenterology, Institute of Surgery Research, Daping Hospital, Third Military Medical University, Chongqing, China.
authors.forename: Y-L
authors.initials: YL
authors.lastname: Wei
authors.affiliation: Department of Gastroenterology, Institute of Surgery Research, Daping Hospital, Third Military Medical University, Chongqing, China.
authors.forename: C-H
authors.initials: CH
authors.lastname: Lan
authors.affiliation: Department of Urology, Institute of Surgery Research, Daping Hospital, Third Military Medical University, Chongqing, China.
authors.forename: J
authors.initials: J
authors.lastname: Jiang
authors.affiliation: Center for Neuroscience, Shantou University Medical College, Shantou, China.
authors.forename: X-J
authors.initials: XJ
authors.lastname: Yang
authors.affiliation: Department of Pathology, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA, USA.
authors.forename: P-D
authors.initials: PD
authors.lastname: Liu
authors.affiliation: Department of Gastroenterology, Institute of Surgery Research, Daping Hospital, Third Military Medical University, Chongqing, China.
authors.forename: D-F
authors.identifier: 0000000155741760
authors.initials: DF
authors.lastname: Chen
authors.affiliation: Department of Gastroenterology, Institute of Surgery Research, Daping Hospital, Third Military Medical University, Chongqing, China.
authors.forename: B
authors.initials: B
authors.lastname: Wang
mesh_terms: D000818:Animals; D006528:Carcinoma, Hepatocellular / Q000235:genetics / Q000473:pathology*; D015536:Down-Regulation; D019008:Drug Resistance, Neoplasm / Q000235:genetics*; D015972:Gene Expression Regulation, Neoplastic; D056466:Histone Demethylases / Q000235:genetics / Q000502:physiology*; D006801:Humans; D008113:Liver Neoplasms / Q000235:genetics / Q000473:pathology*; D008297:Male; D051379:Mice; D008819:Mice, Nude; D014411:Neoplastic Stem Cells / Q000378:metabolism / Q000473:pathology*; D043562:Receptors, G-Protein-Coupled / Q000378:metabolism; D014407:Tumor Cells, Cultured; D060449:Wnt Signaling Pathway / Q000235:genetics; D051176:beta Catenin / Q000378:metabolism*
chemical_list: C116884:LGR5 protein, human; D043562:Receptors, G-Protein-Coupled; D051176:beta Catenin; D056466:Histone Demethylases; C495195:KDM1A protein, human