SDHB knockout and succinate accumulation are insufficient for tumorigenesis but dual SDHB/NF1 loss yields SDHx-like pheochromocytomas Cell reports (Mouse) Synthetic lethality of cyclin-dependent kinase inhibitor Dinaciclib with VHL-deficiency allows for selective targeting of clear cell renal cell carcinoma Cell cycle (Georgetown, Tex.) (WB, Human)Īrmstrong N, Storey CM, Noll SE et al. Matho C VHL-P138R and VHL-L163R Novel Variants: Mechanisms of VHL Pathogenicity Involving HIF-Dependent and HIF- Independent Actions Front. Wolf C, Smith S, van Wijk SJL Zafirlukast Induces VHL- and HIF-2alpha-Dependent Oxidative Cell Death in 786-O Clear Cell Renal Carcinoma Cells International journal of molecular sciences (WB) Stat5b inhibition blocks proliferation and tumorigenicity of glioblastoma stem cells derived from a de novo murine brain cancer model American journal of cancer research (WB) Berberine reduces hepatic ceramide levels to improve insulin resistance in HFD-fed mice by inhibiting HIF-2 alpha Biomedicine & pharmacotherapy = Biomedecine & pharmacotherapie (IHC-P, WB, ICC/IF, Human, Mouse) HIF inhibitor 32-134D eradicates murine hepatocellular carcinoma in combination with anti-PD1 therapy J Clin Invest 44597 (WB, ChIP, Human, Mouse) Adipocyte HIF2 alpha functions as a thermostat via PKA C alpha regulation in beige adipocytes Nature communications (IHC, Mouse) Contribution of HIF-P4H isoenzyme inhibition to metabolism indicates major beneficial effects being conveyed by HIF-P4H-2 antagonism Journal of Biological Chemistry (WB, Mouse) Regulatory mechanisms of hypoxia-inducible factor 1 activity: Two decades of knowledge. Koyasu, S., Kobayashi, M., Goto, Y., Hiraoka, M., & Harada, H. Differential Roles of Hypoxia-Inducible Factor 1 (HIF-1) and HIF-2 in Hypoxic Gene Regulation. Hypoxia inducible factor (HIF) in the tumor microenvironment: friend or foe? Science China Life Sciences. The role of hypoxia in cancer progression, angiogenesis, metastasis, and resistance to therapy. 2.Muz, B., de la Puente, P., Azab, F., & Azab, A. Advances in Experimental Medicine and Biology. Hypoxia, HIF-1, and the pathophysiology of common human diseases. L., Agani, F., Feldser, D., Iyer, N., Kotch, L., Laughner, E., & Yu, A. Once hydroxylated, HIF-2 alpha binds the von Hippel-Lindau tumor suppressor protein (pVHL) for subsequent ubiquitination and proteasomal degradation (5,6). 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). The HIF-2 alpha subunit is rapidly targeted and degraded by the ubiquitin proteasome system under normoxic conditions. Common gene targets for HIF-1 and HIF-2 include VEGFA and GLUT1 (5). 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). 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). 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. 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). 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. 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).
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. 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).