HIF-Prolyl Hydroxylase Domain Proteins (PHDs) in Cancer—Potential Targets for Anti-Tumor Therapy?

SIMPLE SUMMARY: In solid tumors, proliferation of cancer cells typically outpaces the growth of functional vessels. The net result is often an obstructed blood circulation and areas of deprived oxygen (hypoxia). To overcome this acute stress, hypoxia inducible factors (HIFs) stimulate the expression of numerous proteins that will support adaptation to this situation and stimulate further growth, differentiation, and even dissemination. The HIF-response is closely controlled by a class of enzymes known as the HIF prolyl hydroxylases (PHDs). They are true oxygen sensors and directly regulate the activity of HIFs. Although many studies are currently focusing on inhibiting the activity of HIFs in tumors, the role of hypoxia signaling is complex and regulating PHDs in a number of tumor settings might be beneficial. This review gives an overview of the literature on the nature of PHDs in tumor-associated cells and discusses available PHD inhibitors and their potential use as an anti-tumor therapy. ABSTRACT: Solid tumors are typically associated with unbridled proliferation of malignant cells, accompanied by an immature and dysfunctional tumor-associated vascular network. Consequent impairment in transport of nutrients and oxygen eventually leads to a hypoxic environment wherein cells must adapt to survive and overcome these stresses. Hypoxia inducible factors (HIFs) are central transcription factors in the hypoxia response and drive the expression of a vast number of survival genes in cancer cells and in cells in the tumor microenvironment. HIFs are tightly controlled by a class of oxygen sensors, the HIF-prolyl hydroxylase domain proteins (PHDs), which hydroxylate HIFs, thereby marking them for proteasomal degradation. Remarkable and intense research during the past decade has revealed that, contrary to expectations, PHDs are often overexpressed in many tumor types, and that inhibition of PHDs can lead to decreased tumor growth, impaired metastasis, and diminished tumor-associated immune-tolerance. Therefore, PHDs represent an attractive therapeutic target in cancer research. Multiple PHD inhibitors have been developed that were either recently accepted in China as erythropoiesis stimulating agents (ESA) or are currently in phase III trials. We review here the function of HIFs and PHDs in cancer and related therapeutic opportunities.