title: G9a/RelB regulates self-renewal and function of colon-cancer-initiating cells by silencing Let-7b and activating the K-RAS/β-catenin pathway.
abstract: Epigenetic reprogramming has been associated with the functional plasticity of cancer-initiating cells (CICs); however, the regulatory pathway has yet to be elucidated. A siRNA screen targeting known epigenetic genes revealed that G9a profoundly impairs the chemo-resistance, self-renewal and metastasis of CICs obtained from patients with colorectal cancer (CRC). Patients with elevated G9a were shown to face a high risk of relapse and poor survival rates. From a mechanistic perspective, G9a binds with and stabilizes RelB, thereby recruiting DNA methyltransferase 3 on the Let-7b promoter and repressing its expression. This leads to the activation of the K-RAS/β-catenin pathway and regulates self-renewal and function of CICs. These findings indicate that the G9a/RelB/Let-7b axis acts as a critical regulator in the maintenance of CIC phenotypes and is strongly associated with negative clinical outcomes. Thus, these findings may have diagnostic as well as therapeutic implications for the treatment of chemotherapy-resistant or metastatic CRC.
authors.affiliation: Center for Systems Biology, National Taiwan University, Taipei 100, Taiwan.|Department of Dermatology, National Taiwan University Hospital and National Taiwan University College of Medicine, Taipei 100, Taiwan.
authors.forename: Shih-Ting
authors.initials: ST
authors.lastname: Cha
authors.affiliation: Department of Otolaryngology, National Taiwan University Hospital, Taipei 100, Taiwan.
authors.forename: Ching-Ting
authors.initials: CT
authors.lastname: Tan
authors.affiliation: Graduate Institute of Oral Biology, School of Dentistry, National Taiwan University, Taipei 100, Taiwan.|Department of Dentistry, National Taiwan University Hospital, Taipei 100, Taiwan.
authors.forename: Cheng-Chi
authors.initials: CC
authors.lastname: Chang
authors.affiliation: Department of Dermatology, National Taiwan University Hospital and National Taiwan University College of Medicine, Taipei 100, Taiwan.
authors.forename: Chia-Yu
authors.initials: CY
authors.lastname: Chu
authors.affiliation: Department of Urology, Wan Fang Hospital, Taipei Medical University, Taipei 110, Taiwan.
authors.forename: Wei-Jiunn
authors.initials: WJ
authors.lastname: Lee
authors.affiliation: Department of Surgery, National Taiwan University Hospital, Taipei 100, Taiwan.
authors.forename: Been-Zen
authors.initials: BZ
authors.lastname: Lin
authors.affiliation: Department of Surgery, National Taiwan University Hospital, Taipei 100, Taiwan.|Department of Medical Education &Bioethics, Graduate Institute of Medical Education &Bioethics, National Taiwan University College of Medicine, Taipei 100, Taiwan.
authors.forename: Ming-Tsan
authors.initials: MT
authors.lastname: Lin
authors.affiliation: Institute of Biochemical Science, College of Life Science, National Taiwan University, Taipei 100, Taiwan.|Graduate Institute of Medicine, College of Medicine, Kaohsiung Medical University, Kaohsiung, 807, Taiwan.
authors.forename: Min-Liang
authors.initials: ML
authors.lastname: Kuo
mesh_terms: D000818:Animals; D003106:Colon / Q000378:metabolism; D015179:Colorectal Neoplasms / Q000378:metabolism* / Q000473:pathology; D019008:Drug Resistance, Neoplasm / Q000235:genetics*; D020868:Gene Silencing / Q000502:physiology; D011905:Genes, ras / Q000235:genetics; D006649:Histocompatibility Antigens / Q000235:genetics*; D011495:Histone-Lysine N-Methyltransferase / Q000235:genetics*; D006801:Humans; D051379:Mice; D035683:MicroRNAs / Q000235:genetics*; D014411:Neoplastic Stem Cells / Q000378:metabolism; D010641:Phenotype; D051841:Transcription Factor RelB / Q000235:genetics*; D060449:Wnt Signaling Pathway / Q000235:genetics / Q000502:physiology; D051176:beta Catenin / Q000235:genetics / Q000378:metabolism
chemical_list: D006649:Histocompatibility Antigens; D035683:MicroRNAs; C497593:RELB protein, human; C497594:Relb protein, mouse; D051176:beta Catenin; C487931:mirnlet7 microRNA, human; C542687:mirnlet7 microRNA, mouse; D051841:Transcription Factor RelB; C445405:EHMT2 protein, human; C533711:G9a protein, mouse; D011495:Histone-Lysine N-Methyltransferase