title: let-7 Modulates Chromatin Configuration and Target Gene Repression through Regulation of the ARID3B Complex.
abstract: Let-7 is crucial for both stem cell differentiation and tumor suppression. Here, we demonstrate a chromatin-dependent mechanism of let-7 in regulating target gene expression in cancer cells. Let-7 directly represses the expression of AT-rich interacting domain 3B (ARID3B), ARID3A, and importin-9. In the absence of let-7, importin-9 facilitates the nuclear import of ARID3A, which then forms a complex with ARID3B. The nuclear ARID3B complex recruits histone demethylase 4C to reduce histone 3 lysine 9 trimethylation and promotes the transcription of stemness factors. Functionally, expression of ARID3B is critical for the tumor initiation in let-7-depleted cancer cells. An inverse association between let-7 and ARID3A/ARID3B and prognostic significance is demonstrated in head and neck cancer patients. These results highlight a chromatin-dependent mechanism where let-7 regulates cancer stemness through ARID3B.
authors.affiliation: Institute of Clinical Medicine, National Yang-Ming University, No. 155, Section 2, Li-Nong Street, Taipei 11221, Taiwan.
authors.forename: Tsai-Tsen
authors.initials: TT
authors.lastname: Liao
authors.affiliation: Institute of Clinical Medicine, National Yang-Ming University, No. 155, Section 2, Li-Nong Street, Taipei 11221, Taiwan.
authors.forename: Wen-Hao
authors.initials: WH
authors.lastname: Hsu
authors.affiliation: Institute of Clinical Medicine, National Yang-Ming University, No. 155, Section 2, Li-Nong Street, Taipei 11221, Taiwan.
authors.forename: Chien-Hsin
authors.initials: CH
authors.lastname: Ho
authors.affiliation: The Ph.D. Program for Translational Medicine, College of Medical Science and Technology, Taipei Medical University, No. 250, Wuxing Street, Taipei 11031, Taiwan.
authors.forename: Wei-Lun
authors.initials: WL
authors.lastname: Hwang
authors.affiliation: Institute of Clinical Medicine, National Yang-Ming University, No. 155, Section 2, Li-Nong Street, Taipei 11221, Taiwan.
authors.forename: Hsin-Yi
authors.initials: HY
authors.lastname: Lan
authors.affiliation: Institute of Clinical Medicine, National Yang-Ming University, No. 155, Section 2, Li-Nong Street, Taipei 11221, Taiwan.
authors.forename: Ting
authors.initials: T
authors.lastname: Lo
authors.affiliation: Graduate Institute of Oral Biology, School of Dentistry, National Taiwan University, No. 1, Changde Street, Taipei 10048, Taiwan.
authors.forename: Cheng-Chi
authors.initials: CC
authors.lastname: Chang
authors.affiliation: Department of Otolaryngology, Taipei Veterans General Hospital, No. 201, Section 2, Shih-Pai Road, Taipei 11217, Taiwan.
authors.forename: Shyh-Kuan
authors.initials: SK
authors.lastname: Tai
authors.affiliation: Institute of Clinical Medicine, National Yang-Ming University, No. 155, Section 2, Li-Nong Street, Taipei 11221, Taiwan; Institute of Biotechnology in Medicine, National Yang-Ming University, No. 155, Section 2, Li-Nong Street, Taipei 11221, Taiwan; Genomic Research Center, National Yang-Ming University, No. 155, Section 2, Li-Nong Street, Taipei 11221, Taiwan; Division of Medical Oncology, Department of Oncology, Taipei Veterans General Hospital, No. 201, Section 2, Shih-Pai Road, Taipei 11217, Taiwan; Genomic Research Center, Academia Sinica, No. 128, Section 2, Academia Road, Taipei 11529, Taiwan. Electronic address: mhyang2@vghtpe.gov.tw.
authors.forename: Muh-Hwa
authors.initials: MH
authors.lastname: Yang
mesh_terms: D000818:Animals; D001483:Base Sequence; D002460:Cell Line; D002843:Chromatin / Q000378:metabolism; D004268:DNA-Binding Proteins / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D005260:Female; D006657:Histones / Q000378:metabolism; D006801:Humans; D028884:Karyopherins / Q000737:chemistry / Q000235:genetics / Q000378:metabolism; D051379:Mice; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D035683:MicroRNAs / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D009369:Neoplasms / Q000378:metabolism / Q000401:mortality / Q000473:pathology; D050814:Octamer Transcription Factor-3 / Q000235:genetics; D016376:Oligonucleotides, Antisense / Q000378:metabolism; D034622:RNA Interference; D016415:Sequence Alignment; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism; D059467:Transcriptome; D014183:Transplantation, Heterologous
chemical_list: C490798:ARID3A protein, human; C120893:ARID3B protein, human; D002843:Chromatin; D004268:DNA-Binding Proteins; D006657:Histones; C587011:IPO9 protein, human; D028884:Karyopherins; D035683:MicroRNAs; D050814:Octamer Transcription Factor-3; D016376:Oligonucleotides, Antisense; C494173:POU5F1 protein, human; D014157:Transcription Factors; C487931:mirnlet7 microRNA, human