The family of HIF prolyl hydroxylase enzymes (PHDs) is known for their function of post-translationally regulating hypoxia-inducible transcription factors (HIFs) in oxygen-dependent manner. HIFs are the key transcription factors mediating the cellular responses to low oxygen concentration, i.e. hypoxia, by activating target genes that in turn drive the cellular adaptation. Among the PHDs, PHD3 shows particularly high expression in clear cell renal cell carcinoma (ccRCC) tumors and derived cell lines. However, the role of PHD3 expression in ccRCC has remained elusive. 

In this thesis work, PHD3 is shown to have widespread functions in ccRCC. PHD3 regulates glucose metabolism and lactate production, as well as number of translational machinery components and activation of mTOR downstream signaling. PHD3 has previously been linked to cell cycle progression and my work extended the knowledge on PHD3 enhancing cell cycle progression, proliferation and 3D colony formation in ccRCC cells. PHD3 was also found to regulate cell migration and several proteins related to cytoskeleton and attachment. Moreover, the work revealed a novel mechanism for HIF-2α post-transcriptional regulation as PHD3 was found to maintain HIF-2α mRNA level in ccRCC cells. This new relation of PHD3 and HIF2A was further examined in clinical ccRCC tumor samples, in which a positive correlation of HIF2A and PHD3 expression was demonstrated. The results indicate a substantial role for PHD3 in promoting ccRCC growth and other processes linked to malignant progression