Research Papers:

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

Nikki A. Evensen _, Yiyi Li, Cem Kuscu, Jingxuan Liu, Jillian Cathcart, Anna Banach, Qian Zhang, Ellen Li, Sonia Joshi, Jie Yang, Paula I. Denoya, Silvia Pastorekova, Stanley Zucker, Kenneth R. Shroyer and Jian Cao

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Oncotarget. 2015; 6:20723-20739. https://doi.org/10.18632/oncotarget.3978

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Nikki A. Evensen1,9,*, Yiyi Li1,8,*, Cem Kuscu1,10, Jingxuan Liu2, Jillian Cathcart1, Anna Banach1, Qian Zhang1, Ellen Li3, Sonia Joshi1, Jie Yang4, Paula I Denoya5, Silvia Pastorekova6, Stanley Zucker7, Kenneth R. Shroyer2, Jian Cao1,2

1Department of Medicine/Division of Cancer Prevention, Stony Brook University, Stony Brook, NY 11794, USA

2Department of Pathology, Stony Brook University, Stony Brook, NY 11794, USA

3Department of Medicine/Division of Gastroenterology, Stony Brook University, Stony Brook, NY 11794, USA

4Department of Preventative Medicine, Stony Brook University, Stony Brook, NY 11794, USA

5Department of Surgery, Stony Brook University, Stony Brook, NY 11794, USA

6Department of Molecular Medicine, Institute of Virology, Slovak Academy of Sciences, Bratislava 84505, Slovak Republic

7Veterans Affairs Medical Center, Northport, NY 11768, USA

8Department of Radiation Oncology, Nanfang Hospital, Southern Medical University, Guangzhou 510515, China

9Department of Pediatrics, NYU Medical School, New York, NY 10016, USA

10Department 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: [email protected]

Keywords: KIAA1199/CEMIP, migration, invasion, HIF-2α

Received: February 26, 2015     Accepted: April 30, 2015     Published: May 13, 2015


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.

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