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Hypoxia promotes colon cancer dissemination through up-regulation of cell migration-inducing protein (CEMIP)

2015; Impact Journals LLC; Volume: 6; Issue: 24 Linguagem: Inglês

10.18632/oncotarget.3978

1949-2553

Nikki A. Evensen, Yiyi Li, Cem Kuscu, Jingxuan Liu, Jillian Cathcart, Anna Banach, QIAN ZHANG, Ellen Li, Sonia Joshi, Jie Yang, Paula Denoya, Silvia Pastoreková, Stanley Zucker, Kenneth R. Shroyer, Jian Cao,

Cancer-related Molecular Pathways

// Nikki A. Evensen 1, 9, * , Yiyi Li 1, 8, * , Cem Kuscu 1, 10 , Jingxuan Liu 2 , Jillian Cathcart 1 , Anna Banach 1 , Qian Zhang 1 , Ellen Li 3 , Sonia Joshi 1 , Jie Yang 4 , Paula I Denoya 5 , Silvia Pastorekova 6 , Stanley Zucker 7 , Kenneth R. Shroyer 2 , Jian Cao 1, 2 1 Department of Medicine/Division of Cancer Prevention, Stony Brook University, Stony Brook, NY 11794, USA 2 Department of Pathology, Stony Brook University, Stony Brook, NY 11794, USA 3 Department of Medicine/Division of Gastroenterology, Stony Brook University, Stony Brook, NY 11794, USA 4 Department of Preventative Medicine, Stony Brook University, Stony Brook, NY 11794, USA 5 Department of Surgery, Stony Brook University, Stony Brook, NY 11794, USA 6 Department of Molecular Medicine, Institute of Virology, Slovak Academy of Sciences, Bratislava 84505, Slovak Republic 7 Veterans Affairs Medical Center, Northport, NY 11768, USA 8 Department of Radiation Oncology, Nanfang Hospital, Southern Medical University, Guangzhou 510515, China 9 Department of Pediatrics, NYU Medical School, New York, NY 10016, USA 10 Department of Biochemistry and Molecular Genetics, University of Virginia, Charlottesville, VA 22908, USA * These authors have contributed equally to this work Correspondence to: Jian Cao, e-mail: Jian.Cao@stonybrookmedicine.edu Keywords: KIAA1199/CEMIP, migration, invasion, HIF-2α Received: February 26, 2015 Accepted: April 30, 2015 Published: May 13, 2015 ABSTRACT Hypoxic stress drives cancer progression by causing a transcriptional reprogramming. Recently, KIAA1199 was discovered to be a ce ll- m igration i nducing p rotein (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.