MKP-3 induced by hypoxia negatively regulates HIF-1α in colon cancer.

초록

Hypoxia is a hallmark feature of the tumor microenvironment. HIF-1a subunit plays a critical role in the adaptive cellular response to low-oxygen tensions in hypoxic tumor cells. The HIF-1a is a phosphorylated protein and its phosphorylation is involved in HIF-1a stabilization as well as in the regulation of HIF-1a transcriptional activity. HIF-1a activation is initiated by several factors including MAPK superfamily. MAPK phosphatases 3 (MKP-3) is a cytoplasmic dual-specificity phosphatase specific for the Erk1/2. In this study, we found that hypoxia induced MKP-3 protein levels in a HIF-1a-dependent manner. We also show that siRNA-mediated knockdown of MKP-3 enhanced phospho-Erk1/2 and HIF-1a levels that is rescued by MEK inhibitor in hypoxia. Conversely, over-expression of MKP-3 suppressed phospho-Erk1/2, HIF-1a levels, and the expression of hypoxia responsive genes in hypoxia. These findings suggest that over-expression of MKP-3 could suppress cellular adaptation to hypoxia through regulating Erk1/2 signaling and be a prominent therapeutic target for the treatment of cancer.