title: The nucleolar protein NIFK promotes cancer progression via CK1α/β-catenin in metastasis and Ki-67-dependent cell proliferation.
abstract: Nucleolar protein interacting with the FHA domain of pKi-67 (NIFK) is a Ki-67-interacting protein. However, its precise function in cancer remains largely uninvestigated. Here we show the clinical significance and metastatic mechanism of NIFK in lung cancer. NIFK expression is clinically associated with poor prognosis and metastasis. Furthermore, NIFK enhances Ki-67-dependent proliferation, and promotes migration, invasion in vitro and metastasis in vivo via downregulation of casein kinase 1α (CK1α), a suppressor of pro-metastatic TCF4/β-catenin signaling. Inversely, CK1α is upregulated upon NIFK knockdown. The silencing of CK1α expression in NIFK-silenced cells restores TCF4/β-catenin transcriptional activity, cell migration, and metastasis. Furthermore, RUNX1 is identified as a transcription factor of CSNK1A1 (CK1α) that is negatively regulated by NIFK. Our results demonstrate the prognostic value of NIFK, and suggest that NIFK is required for lung cancer progression via the RUNX1-dependent CK1α repression, which activates TCF4/β-catenin signaling in metastasis and the Ki-67-dependent regulation in cell proliferation.
authors.affiliation: Genomics Research Center, Academia Sinica, Taipei, Taiwan.
authors.forename: Tsung-Chieh
authors.initials: TC
authors.lastname: Lin
authors.affiliation: Genomics Research Center, Academia Sinica, Taipei, Taiwan.
authors.forename: Chia-Yi
authors.initials: CY
authors.lastname: Su
authors.affiliation: Institute of Biological Chemistry, Academia Sinica, Taipei, Taiwan.
authors.forename: Pei-Yu
authors.initials: PY
authors.lastname: Wu
authors.affiliation: Genomics Research Center, Academia Sinica, Taipei, Taiwan.
authors.forename: Tsung-Ching
authors.initials: TC
authors.lastname: Lai
authors.affiliation: Institute of Biological Chemistry, Academia Sinica, Taipei, Taiwan.|Institute of Biochemical Sciences, National Taiwan University, Taipei, Taiwan.
authors.forename: Wen-An
authors.initials: WA
authors.lastname: Pan
authors.affiliation: Genomics Research Center, Academia Sinica, Taipei, Taiwan.
authors.forename: Yi-Hua
authors.initials: YH
authors.lastname: Jan
authors.affiliation: Genomics Research Center, Academia Sinica, Taipei, Taiwan.
authors.forename: Yu-Chang
authors.initials: YC
authors.lastname: Chang
authors.affiliation: Department of Medical Research and Education, Taipei Medical University-Shuang Ho Hospital, New Taipei City, Taiwan.
authors.forename: Chi-Tai
authors.initials: CT
authors.lastname: Yeh
authors.affiliation: Department of Pathology, Taipei Medical University Hospital, Taipei Medical University, Taipei, Taiwan.|Department of Pathology, College of Medicine, Taipei Medical University, Taipei, Taiwan.
authors.forename: Chi-Long
authors.initials: CL
authors.lastname: Chen
authors.affiliation: Department of Medical Education and Research, Kaohsiung Veterans General, Kaohsiung, Taiwan.
authors.forename: Luo-Ping
authors.initials: LP
authors.lastname: Ger
authors.affiliation: Department of Surgery, Kaohsiung Veterans General, Kaohsiung, Taiwan.|Department of Emergency Medicine, Kaohsiung Veterans General, Kaohsiung, Taiwan.
authors.forename: Hong-Tai
authors.initials: HT
authors.lastname: Chang
authors.affiliation: Department of Internal Medicine, Kaohsiung Medical University Hospital, Kaohsiung, Taiwan.
authors.forename: Chih-Jen
authors.initials: CJ
authors.lastname: Yang
authors.affiliation: Department of Internal Medicine, Kaohsiung Medical University Hospital, Kaohsiung, Taiwan.
authors.forename: Ming-Shyan
authors.identifier: http://orcid.org/0000-0001-8180-2213
authors.initials: MS
authors.lastname: Huang
authors.affiliation: Graduate Institute of Clinical Medicine, Kaohsiung Medical University, Kaohsiung, Taiwan.|Center for Infectious Disease and Cancer Research, Kaohsiung Medical University, Kaohsiung, Taiwan.
authors.forename: Yu-Peng
authors.initials: YP
authors.lastname: Liu
authors.affiliation: Graduate Institute of Clinical Medicine, College of Medicine, Taipei Medical University, Taipei, Taiwan.
authors.forename: Yuan-Feng
authors.initials: YF
authors.lastname: Lin
authors.affiliation: Department of Medicine, University of California, San Diego, San Diego, United States.
authors.forename: John Y-J
authors.initials: JY
authors.lastname: Shyy
authors.affiliation: Genomics Research Center, Academia Sinica, Taipei, Taiwan.|Institute of Biological Chemistry, Academia Sinica, Taipei, Taiwan.
authors.forename: Ming-Daw
authors.initials: MD
authors.lastname: Tsai
authors.affiliation: Genomics Research Center, Academia Sinica, Taipei, Taiwan.
authors.forename: Michael
authors.identifier: http://orcid.org/0000-0001-8529-9213
authors.initials: M
authors.lastname: Hsiao
mesh_terms: D000818:Animals; D047390:Casein Kinase II / Q000378:metabolism; D049109:Cell Proliferation; D004195:Disease Models, Animal; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins / Q000378:metabolism*; D019394:Ki-67 Antigen / Q000378:metabolism; D007723:Korea; D008175:Lung Neoplasms / Q000473:pathology*; D051379:Mice; D009362:Neoplasm Metastasis; D009687:Nuclear Proteins / Q000378:metabolism*; D051176:beta Catenin / Q000378:metabolism*
chemical_list: D047908:Intracellular Signaling Peptides and Proteins; D019394:Ki-67 Antigen; C492406:NIFK protein, human; D009687:Nuclear Proteins; D051176:beta Catenin; C570325:CSNK2A1 protein, human; D047390:Casein Kinase II
keywords: NIFK; casein kinase 1 alpha; cell biology; human; lung cancer; metastasis; runx1