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PHDs in Epigenetics and Disease

The prolyl hydroxylase domain (PHD) protein family consists of three closely related oxygen-sensing enzymes—PHD1 (EGLN2), PHD2 (EGLN1), and PHD3 (EGLN3)—that regulate the cellular response to oxygen availability. Under normal oxygen conditions, these enzymes hydroxylate hypoxia-inducible factor (HIF) proteins, targeting them for degradation and preventing activation of hypoxia-responsive genes. When oxygen levels are low, PHD activity decreases, allowing HIF to accumulate and induce the expression of genes involved in erythropoiesis, angiogenesis, metabolism, and cell survival. Because of their central role in oxygen homeostasis, PHD proteins are important therapeutic targets in diseases such as anemia, ischemic disorders, and cancer, and inhibitors of PHD enzymes have been developed to stimulate HIF signaling for the treatment of certain forms of chronic kidney disease–associated anemia.

 
Protein / Family Epigenetic Function Disease Association Key Publications Key Products
ARNT (HIF-1β) Participates in transcriptional regulation by enabling HIF binding to hypoxia-response elements and recruitment of transcriptional coactivators. Cancer and metabolic disorders. Hou et al., Mol Med Rep. 2026.
CREBBP (CBP) Histone acetyltransferase and transcriptional coactivator. Cooperates with HIF-α to activate hypoxia-responsive genes. Cancer and Rubinstein-Taybi syndrome. Wang et al., J Neuropathol Exp Neurol. 2026.
CUL2 (Cullin-2) Scaffold protein of the VHL E3 ubiquitin ligase complex. Indirect transcriptional effects through regulation of HIF protein stability. Cancer and VHL-associated tumors. Mariappan et al., Curr Drug Targets. 2026.
EGLN1 (PHD2) Principal oxygen sensor. Hydroxylates HIF-1α and HIF-2α, promoting VHL-dependent degradation under normoxia. Cancer, pulmonary hypertension, cardiovascular disease, erythrocytosis, and metabolic disease. Maksiutenko et al., Front Biosci. 2026
EGLN2 (PHD1) HIF prolyl hydroxylase that contributes to oxygen-dependent HIF regulation. Indirect transcriptional and chromatin effects through HIF regulation. Cancer, metabolic disorders, and erythrocytosis Zhang et al., Theriogenology. 2026
EGLN3 (PHD3) Oxygen-sensitive prolyl hydroxylase that regulates HIF-α, with important roles in hypoxic adaptation and cell survival. Indirect epigenetic/transcriptional effects through HIF stabilization and regulation of hypoxia-responsive gene programs. Cancer, ischemic disease, cardiovascular disease, and erythrocytosis. Jin et al., Arterioscler Thromb Vasc Biol. 2026
EP300 (p300) HIF transcriptional coactivator closely related to CBP; binds HIF-α transactivation domains. Cancer and Rubinstein-Taybi syndrome. Jiang et al., Cell Press. 2026.
FH (Fumarate hydratase) TCA cycle enzyme producing fumarate. Fumarate can inhibit PHD enzymes when accumulated.Fumarate accumulation can inhibit 2OG-dependent epigenetic enzymes, including DNA and histone demethylases, producing broad epigenetic effects. Hereditary leiomyomatosis and renal cell cancer (HLRCC). Saad et al., Nat Rev Clin Oncol. 2026.
IDH1 Cytosolic isocitrate dehydrogenase. Produces 2-oxoglutarate, a required PHD cosubstrate. Metabolically regulates availability of a key cofactor for 2OG-dependent dioxygenases, potentially influencing epigenetic enzymes as well as PHDs. Glioma, acute myeloid leukemia and chondrosarcoma. Hou et al., Int J Lab Hematol. 2025.
IDH2 Mitochondrial isocitrate dehydrogenase; contributes to cellular 2-oxoglutarate metabolism. Controls metabolite availability for 2OG-dependent epigenetic enzymes and oxygen sensors. Acute myeloid leukemia, glioma, and chondrosarcoma. Fang et al., MedComm. 2026.

 

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