title: NKX6.1 functions as a metastatic suppressor through epigenetic regulation of the epithelial-mesenchymal transition.
abstract: The transcription factor NKX6.1 (NK6 homeobox 1) is important in the development of pancreatic β-cells and neurons. Although recent publications show that NKX6.1 is hypermethylated and downregulated during tumorigenesis, the function of NKX6.1 in carcinogenesis remains elusive. Here, we address the metastasis suppressor function of human NKX6.1 using cell, animal and clinical analyses. Our data show that NKX6.1 represses tumor formation and metastatic ability both in vitro and in vivo. Mechanistically, NKX6.1 suppresses cell invasion by inhibiting the epithelial-to-mesenchymal transition (EMT). NKX6.1 directly enhances the mRNA level of E-cadherin by recruiting BAF155 coactivator and represses that of vimentin and N-cadherin by recruiting RBBP7 (retinoblastoma binding protein 7) corepressor. Clinical cancer tumors with metastasis show low NKX6.1 protein expression coinciding with low E-cadherin and high vimentin expression. Our results demonstrate that NKX6.1 functions as an EMT suppressor by interacting with different epigenetic modifiers, making it a potential novel therapeutic option.
authors.affiliation: Graduate Institute of Life Sciences, National Defense Medical Center, Taipei, Taiwan, Republic of China.
authors.forename: H-J
authors.initials: HJ
authors.lastname: Li
authors.affiliation: Department and Graduate Institute of Microbiology and Immunology, National Defense Medical Center, Taipei, Taiwan, Republic of China.
authors.forename: P-N
authors.initials: PN
authors.lastname: Yu
authors.affiliation: Graduate Institute of Life Sciences, National Defense Medical Center, Taipei, Taiwan, Republic of China.
authors.forename: K-Y
authors.initials: KY
authors.lastname: Huang
authors.affiliation: Department of Obstetrics and Gynecology, Tri-Service General Hospital, National Defense Medical Center, Taipei, Taiwan, Republic of China.
authors.forename: H-Y
authors.initials: HY
authors.lastname: Su
authors.affiliation: Department of Medical Research, Taichung Veterans General Hospital, Taipei, Taiwan, Republic of China.
authors.forename: T-H
authors.initials: TH
authors.lastname: Hsiao
authors.affiliation: Department and Graduate Institute of Microbiology and Immunology, National Defense Medical Center, Taipei, Taiwan, Republic of China.
authors.forename: C-P
authors.initials: CP
authors.lastname: Chang
authors.affiliation: Department of Obstetrics and Gynecology, Tri-Service General Hospital, National Defense Medical Center, Taipei, Taiwan, Republic of China.
authors.forename: M-H
authors.initials: MH
authors.lastname: Yu
authors.affiliation: Graduate Institute of Life Sciences, National Defense Medical Center, Taipei, Taiwan, Republic of China.|Department and Graduate Institute of Microbiology and Immunology, National Defense Medical Center, Taipei, Taiwan, Republic of China.
authors.forename: Y-W
authors.initials: YW
authors.lastname: Lin
mesh_terms: D000818:Animals; D015820:Cadherins / Q000096:biosynthesis / Q000235:genetics*; D045744:Cell Line, Tumor; D019175:DNA Methylation / Q000235:genetics; D044127:Epigenesis, Genetic; D058750:Epithelial-Mesenchymal Transition / Q000187:drug effects / Q000235:genetics*; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D016147:Genes, Tumor Suppressor; D018398:Homeodomain Proteins / Q000235:genetics* / Q000378:metabolism; D006801:Humans; D051379:Mice; D009361:Neoplasm Invasiveness / Q000235:genetics; D012333:RNA, Messenger / Q000235:genetics; D056524:Retinoblastoma-Binding Protein 7 / Q000235:genetics*; D014157:Transcription Factors / Q000235:genetics*; D014746:Vimentin / Q000008:administration & dosage
chemical_list: D015820:Cadherins; D018398:Homeodomain Proteins; C105201:NKX6-1 protein, human; C490746:RBBP7 protein, human; D012333:RNA, Messenger; D056524:Retinoblastoma-Binding Protein 7; C101681:SMARCC1 protein, human; D014157:Transcription Factors; D014746:Vimentin