The protein Hypoxia-Inducible Factor 2-alpha (HIF-2α) helps our cells survive when oxygen levels drop. As a transcription factor, it controls genes that manage cellular adaptation to low-oxygen, or hypoxic, conditions. As part of the HIF protein family, HIF-2α is involved in many normal bodily processes. Its activity is important for maintaining health but can also contribute to various diseases. Understanding HIF-2α provides insight into human biology and offers pathways for new medical treatments.
The Oxygen Sensing Mechanism of HIF-2α
The amount of HIF-2α in a cell is controlled by oxygen availability. In normal oxygen levels (normoxia), HIF-2α is produced but immediately marked for destruction. This is initiated by prolyl hydroxylase domain (PHD) enzymes, which use oxygen to add hydroxyl groups to the HIF-2α protein in a process called hydroxylation.
This hydroxylation allows the von Hippel-Lindau (VHL) tumor suppressor protein to recognize and bind to HIF-2α. VHL is part of a complex that attaches ubiquitin molecules to HIF-2α, signaling it for breakdown by the cell’s proteasome. This process keeps HIF-2α levels low under normal oxygen conditions.
When oxygen levels fall, PHD enzymes become less active. Without the hydroxylation tag, HIF-2α escapes recognition by VHL and is no longer targeted for degradation. The stable HIF-2α protein accumulates and travels to the cell’s nucleus, where it partners with another protein, HIF-1β (also known as ARNT). This complex binds to DNA sequences called hypoxia-response elements (HREs), activating genes that help the cell adapt.
Normal Physiological Roles of HIF-2α
The genes activated by HIF-2α are involved in several bodily functions necessary for health. One primary role is in erythropoiesis, the production of red blood cells. HIF-2α stimulates the kidneys and liver to produce erythropoietin (EPO), a hormone that signals the bone marrow to increase red blood cell production for oxygen transport.
HIF-2α also contributes to angiogenesis, the development and maturation of blood vessels. It triggers the expression of genes like vascular endothelial growth factor (VEGF) to stimulate new blood vessel formation. This is important for building the circulatory system during embryonic development and for adult tissue repair. Without HIF-2α, mouse embryos show severe defects in blood vessel development.
HIF-2α is also involved in regulating iron metabolism. Iron is a component of hemoglobin, the oxygen-carrying protein in red blood cells, connecting its availability to erythropoiesis. HIF-2α influences genes that control iron absorption, transport, and storage, ensuring enough is available for new red blood cells.
HIF-2α in Disease Development
The functions of HIF-2α can be co-opted or dysregulated in diseases like cancer. Many solid tumors create hypoxic microenvironments as they outgrow their blood supply. In these zones, cancer cells stabilize HIF-2α, which activates genes that help the tumor survive and grow. This includes promoting angiogenesis to create new blood vessels that supply the tumor with nutrients and oxygen.
HIF-2α is a primary driver of clear cell renal cell carcinoma (ccRCC), the most common kidney cancer. In most ccRCC cases, the VHL gene is mutated. Without a functional VHL protein, HIF-2α is not degraded even in normal oxygen, leading to its constant accumulation. This drives gene expression that contributes to tumor growth and metastasis.
HIF-2α’s influence extends to other diseases. In some forms of pulmonary hypertension, HIF-2α dysregulation contributes to the remodeling of pulmonary blood vessels, leading to their narrowing and increased resistance to blood flow. Mutations causing overly stable HIF-2α are also linked to familial erythrocytosis, where the body produces too many red blood cells, leading to thicker blood.
Therapeutic Strategies Targeting HIF-2α
Because of its role in diseases like cancer, HIF-2α is an attractive target for drug development. These therapies aim to block HIF-2α activity, cutting off pathways that tumors use to survive. The protein’s structure includes a large internal cavity, allowing for the design of small-molecule drugs that bind to it and disrupt its function. These inhibitors prevent HIF-2α from partnering with HIF-1β, a step required for its activity.
A major development is belzutifan (MK-6482), a first-in-class HIF-2α inhibitor. This oral medication binds to HIF-2α and blocks its ability to form a complex with HIF-1β, preventing the activation of its target genes. Belzutifan has received regulatory approval for treating patients with VHL disease-associated tumors, including ccRCC, central nervous system hemangioblastomas, and pancreatic neuroendocrine tumors.
The success of belzutifan has spurred further research, with clinical trials exploring HIF-2α inhibitors for a broader range of cancers and in combination with other treatments like immunotherapy. These targeted therapies are often better tolerated than traditional chemotherapy, with manageable side effects like anemia and fatigue. The development of these drugs represents a promising advance in oncology, turning an understanding of cellular oxygen sensing into a therapeutic strategy.