Hypoxia contributes to the pathophysiology of human disease, including myocardial and cerebral ischemia, cancer, pulmonary hypertension, congenital heart disease and chronic obstructive pulmonary disease (1). In cancer, and particularly solid tumors, hypoxia plays a critical role in the regulation of genes involved in stem cell renewal, epithelial to mesenchymal transition (EMT), metastasis and angiogenesis. In the tumor microenvironment (TME), hypoxia influences the properties and function of stromal cells (e.g., fibroblasts, endothelial and immune cells) and is a strong determinant of tumor progression (2,3).
HIF-1 or hypoxia inducible factor 1, is a transcription factor commonly referred to as a "master regulator of the hypoxic response" for its central role in the regulation of cellular adaptations to hypoxia. Similarly, HIF-2 alpha plays a role in cellular responses to hypoxia, but whereas HIF-1 alpha is ubiquitously expressed, HIF-2 alpha is predominantly expressed in the vascular endothelium at embryonic stages and after birth in select cells and tissue types (e.g., fibroblasts, hepatocytes and myocytes at 96kDa) (4). Following a similar mechanism to HIF-1 alpha, HIF-2 alpha is stabilized under hypoxic conditions by the formation of a heterodimer with an ARNT/HIF-1 beta subunit. Stable HIF-2 alpha-ARNT/HIF-1 beta heterodimers engage p300/CBP in the nucleus for binding to hypoxic response elements (HREs), inducing transcription, and thus regulation of genes (e.g., EPO, VEGFA). HIF-1 predominantly transactivates genes involved in glycolytic control and pro-apoptotic genes (e.g., LDHA and BNIP3), and HIF-2 regulates the expression of genes involved in invasion and stemness (e.g., MMP2, and OCT4). Common gene targets for HIF-1 and HIF-2 include VEGFA and GLUT1 (5).
The HIF-2 alpha subunit is rapidly targeted and degraded by the ubiquitin proteasome system under normoxic conditions. This process is mediated by oxygen-sensing enzymes, prolyl hydroxylase domain enzymes (PHDs), which catalyze the hydroxylation of key proline residues (Pro-405 and Pro-531) within the oxygen-dependent degradation domain of HIF-2 alpha (5). Once hydroxylated, HIF-2 alpha binds the von Hippel-Lindau tumor suppressor protein (pVHL) for subsequent ubiquitination and proteasomal degradation (5,6).
1. Semenza, G. L., Agani, F., Feldser, D., Iyer, N., Kotch, L., Laughner, E., & Yu, A. (2000). Hypoxia, HIF-1, and the pathophysiology of common human diseases. Advances in Experimental Medicine and Biology.
2.Muz, B., de la Puente, P., Azab, F., & Azab, A. K. (2015). The role of hypoxia in cancer progression, angiogenesis, metastasis, and resistance to therapy. Hypoxia. https://doi.org/10.2147/hp.s93413
3. Huang, Y., Lin, D., & Taniguchi, C. M. (2017). Hypoxia inducible factor (HIF) in the tumor microenvironment: friend or foe? Science China Life Sciences. https://doi.org/10.1007/s11427-017-9178-y
4. Hu, C.-J., Wang, L.-Y., Chodosh, L. A., Keith, B., & Simon, M. C. (2003). Differential Roles of Hypoxia-Inducible Factor 1 (HIF-1) and HIF-2 in Hypoxic Gene Regulation. Molecular and Cellular Biology. https://doi.org/10.1128/mcb.23.24.9361-9374.2003
5. Koh, M. Y., & Powis, G. (2012). Passing the baton: The HIF switch. Trends in Biochemical Sciences. https://doi.org/10.1016/j.tibs.2012.06.004
6. Koyasu, S., Kobayashi, M., Goto, Y., Hiraoka, M., & Harada, H. (2018). Regulatory mechanisms of hypoxia-inducible factor 1 activity: Two decades of knowledge. Cancer Science. https://doi.org/10.1111/cas.13483