Cells in our body are often exposed to hypoxic environment. In such environment, cells regulate respiration and metabolism for adaptation (hypoxic response). Hypoxic response not only plays a key role in maintaining homeostasis, but also in different diseases, such as cancer. Hypoxia-Inducible Factor (HIF) is a central transcription factor in hypoxic response. HIF is promptly up-regulated in hypoxia, and forms adapted cellular state. HIF has multiple target genes, and they coordinately regulate hypoxic response. Recently, HIF specific inhibitor was developed, and it is currently under clinical trial. Alternatively, we have demonstrated that HIF is downregulated, and CREB and NF-kB become activated during chronic phase of hypoxia. However, it remains unclear how the expression pattern of hypoxia-responsive genes changes depending on the timing.
HIF becomes activated by a heterodimer formation of a and b subunits. There are three a subunit isotypes, and they commonly bind to b subunit, ARNT. We have established ARNT knockout (KO) colon cancer HCT116 cells. These cells showed a clear inhibition of typical HIF target gene LDHA. In contrast, MMP1, which is induced under chronic hypoxia, was equally up-regulated in both wild type and KO cells, but its expression level is significantly reduced in KO cells. Altogether, these results indicate that induction of hypoxic genes is dependent on transcription factors which are activated during chronic phase, however, basal expression of them is mediated by a HIF-dependent machinery.