title: Hypoxia promotes colon cancer dissemination through up-regulation of cell migration-inducing protein (CEMIP).
abstract: Hypoxic stress drives cancer progression by causing a transcriptional reprogramming. Recently, KIAA1199 was discovered to be a cell-migration inducing protein (renamed CEMIP) that is upregulated in human cancers. However, the mechanism of induction of CEMIP in cancer was hitherto unknown. Here we demonstrate that hypoxia induces CEMIP expression leading to enhanced cell migration. Immunohistochemistry of human colon cancer tissues revealed that CEMIP is upregulated in cancer cells located at the invasive front or in the submucosa. CEMIP localization inversely correlated with E-cadherin expression, which is characteristic of the epithelial-to-mesenchymal transition. Mechanistically, hypoxia-inducible-factor-2α (HIF-2α), but not HIF-1α binds directly to the hypoxia response element within the CEMIP promoter region resulting in increased CEMIP expression. Functional characterization reveals that CEMIP is a downstream effector of HIF-2α-mediated cell migration. Expression of CEMIP was demonstrated to negatively correlate with the expression of Jarid1A, a histone demethylase that removes methyl groups from H3K4me3 (an activation marker for transcription), resulting in altered gene repression. Low oxygen tension inhibits the function of Jarid1A, leading to increased presence of H3K4me3 within the CEMIP promoter. These results provide insight into the upregulation of CEMIP within cancer and can lead to novel treatment strategies targeting this cancer cell migration-promoting gene.
authors.affiliation: Department of Medicine/Division of Cancer Prevention, Stony Brook University, Stony Brook, NY 11794, USA.|Department of Pediatrics, NYU Medical School, New York, NY 10016, USA.
authors.forename: Nikki A
authors.initials: NA
authors.lastname: Evensen
authors.affiliation: Department of Medicine/Division of Cancer Prevention, Stony Brook University, Stony Brook, NY 11794, USA.|Department of Radiation Oncology, Nanfang Hospital, Southern Medical University, Guangzhou 510515, China.
authors.forename: Yiyi
authors.initials: Y
authors.lastname: Li
authors.affiliation: Department of Medicine/Division of Cancer Prevention, Stony Brook University, Stony Brook, NY 11794, USA.|Department of Biochemistry and Molecular Genetics, University of Virginia, Charlottesville, VA 22908, USA.
authors.forename: Cem
authors.initials: C
authors.lastname: Kuscu
authors.affiliation: Department of Pathology, Stony Brook University, Stony Brook, NY 11794, USA.
authors.forename: Jingxuan
authors.initials: J
authors.lastname: Liu
authors.affiliation: Department of Medicine/Division of Cancer Prevention, Stony Brook University, Stony Brook, NY 11794, USA.
authors.forename: Jillian
authors.initials: J
authors.lastname: Cathcart
authors.affiliation: Department of Medicine/Division of Cancer Prevention, Stony Brook University, Stony Brook, NY 11794, USA.
authors.forename: Anna
authors.initials: A
authors.lastname: Banach
authors.affiliation: Department of Medicine/Division of Cancer Prevention, Stony Brook University, Stony Brook, NY 11794, USA.
authors.forename: Qian
authors.initials: Q
authors.lastname: Zhang
authors.affiliation: Department of Medicine/Division of Gastroenterology, Stony Brook University, Stony Brook, NY 11794, USA.
authors.forename: Ellen
authors.initials: E
authors.lastname: Li
authors.affiliation: Department of Medicine/Division of Cancer Prevention, Stony Brook University, Stony Brook, NY 11794, USA.
authors.forename: Sonia
authors.initials: S
authors.lastname: Joshi
authors.affiliation: Department of Preventative Medicine, Stony Brook University, Stony Brook, NY 11794, USA.
authors.forename: Jie
authors.initials: J
authors.lastname: Yang
authors.affiliation: Department of Surgery, Stony Brook University, Stony Brook, NY 11794, USA.
authors.forename: Paula I
authors.initials: PI
authors.lastname: Denoya
authors.affiliation: Department of Molecular Medicine, Institute of Virology, Slovak Academy of Sciences, Bratislava 84505, Slovak Republic.
authors.forename: Silvia
authors.initials: S
authors.lastname: Pastorekova
authors.affiliation: Veterans Affairs Medical Center, Northport, NY 11768, USA.
authors.forename: Stanley
authors.initials: S
authors.lastname: Zucker
authors.affiliation: Department of Pathology, Stony Brook University, Stony Brook, NY 11794, USA.
authors.forename: Kenneth R
authors.initials: KR
authors.lastname: Shroyer
authors.affiliation: Department of Medicine/Division of Cancer Prevention, Stony Brook University, Stony Brook, NY 11794, USA.|Department of Pathology, Stony Brook University, Stony Brook, NY 11794, USA.
authors.forename: Jian
authors.initials: J
authors.lastname: Cao
mesh_terms: D015687:Cell Hypoxia / Q000502:physiology*; D045744:Cell Line, Tumor; D002465:Cell Movement / Q000502:physiology; D003110:Colonic Neoplasms / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D018450:Disease Progression; D006801:Humans; D006821:Hyaluronoglucosaminidase; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000378:metabolism*; D011401:Promoter Regions, Genetic; D011506:Proteins / Q000235:genetics / Q000378:metabolism*; D015854:Up-Regulation
chemical_list: D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D011506:Proteins; C491433:CEMIP protein, human; D006821:Hyaluronoglucosaminidase
keywords: HIF-2α; KIAA1199/CEMIP; invasion; migration