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, Jian Cao

Research output: Contribution to journalArticle

26 Citations (Scopus)

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-1a 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.

Original languageEnglish (US)
Pages (from-to)20723-20739
Number of pages17
JournalOncotarget
Volume6
Issue number24
DOIs
StatePublished - Jan 1 2015

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Colonic Neoplasms
Cell Movement
Up-Regulation
Proteins
Neoplasms
Hypoxia
Histone Demethylases
Epithelial-Mesenchymal Transition
Response Elements
Cadherins
Genetic Promoter Regions
Transcriptional Activation
Genes
Immunohistochemistry

All Science Journal Classification (ASJC) codes

  • Oncology

Cite this

Hypoxia promotes colon cancer dissemination through up-regulation of cell migration-inducing protein (CEMIP). / Evensen, Nikki A.; Li, Yiyi; Kuscu, Cem; Liu, Jingxuan; Cathcart, Jillian; Banach, Anna; Zhang, Qian; Li, Ellen; Joshi, Sonia; Yang, Jie; Denoya, Paula I.; Pastorekova, Silvia; Zucker, Stanley; Shroyer, Kenneth R.; Cao, Jian.

In: Oncotarget, Vol. 6, No. 24, 01.01.2015, p. 20723-20739.

Research output: Contribution to journalArticle

Evensen, NA, Li, Y, Kuscu, C, Liu, J, Cathcart, J, Banach, A, Zhang, Q, Li, E, Joshi, S, Yang, J, Denoya, PI, Pastorekova, S, Zucker, S, Shroyer, KR & Cao, J 2015, 'Hypoxia promotes colon cancer dissemination through up-regulation of cell migration-inducing protein (CEMIP)', Oncotarget, vol. 6, no. 24, pp. 20723-20739. https://doi.org/10.18632/oncotarget.3978
Evensen, Nikki A. ; Li, Yiyi ; Kuscu, Cem ; Liu, Jingxuan ; Cathcart, Jillian ; Banach, Anna ; Zhang, Qian ; Li, Ellen ; Joshi, Sonia ; Yang, Jie ; Denoya, Paula I. ; Pastorekova, Silvia ; Zucker, Stanley ; Shroyer, Kenneth R. ; Cao, Jian. / Hypoxia promotes colon cancer dissemination through up-regulation of cell migration-inducing protein (CEMIP). In: Oncotarget. 2015 ; Vol. 6, No. 24. pp. 20723-20739.
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