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.