Retention of prolyl hydroxylase PHD2 in the cytoplasm prevents PHD2-induced anchorage-independent carcinoma cell growth.
Cellular oxygen tension is sensed by a family of prolyl hydroxylases (PHD1-3) that regulate the degradation of hypoxia-inducible factors (HIF-1alpha and -2alpha). The PHD2 isoform is considered as the main downregulator of HIF in normoxia. Our previous results have shown that nuclear translocation of PHD2 associates with poorly differentiated tumor phenotype implying that nuclear PHD2 expression is advantageous for tumor growth. Here we show that a pool of PHD2 is shuttled between the nucleus and the cytoplasm. In line with this, accumulation of wild type PHD2 in the nucleus was detected in human colon adenocarcinomas and in cultured carcinoma cells. The PHD2 isoforms showing high nuclear expression increased anchorage-independent carcinoma cell growth. However, retention of PHD2 in the cytoplasm inhibited the anchorage-independent cell growth. A region that inhibits the nuclear localization of PHD2 was identified and the deletion of the region promoted anchorage-independent growth of carcinoma cells. Finally, the cytoplasmic PHD2, as compared with the nuclear PHD2, less efficiently downregulated HIF expression. Forced HIF-1alpha or -2alpha expression decreased and attenuation of HIF expression increased the anchorage-independent cell growth. However, hydroxylase-inactivating mutations in PHD2 had no effect on cell growth. The data imply that nuclear PHD2 localization promotes malignant cancer phenotype.
Jokilehto
Terhi
T
Turku Centre for Biotechnology, University of Turku and Abo Akademi University, Turku, Finland.
Högel
Heidi
H
Heikkinen
Pekka
P
Rantanen
Krista
K
Elenius
Klaus
K
Sundström
Jari
J
Jaakkola
Panu M
PM
D000230:Adenocarcinoma / Q000378:metabolism / Q000473:pathology; D002277:Carcinoma / Q000378:metabolism / Q000473:pathology; D002448:Cell Adhesion / Q000502:physiology; D002467:Cell Nucleus / Q000378:metabolism; D049109:Cell Proliferation; D003110:Colonic Neoplasms / Q000378:metabolism / Q000473:pathology; D003593:Cytoplasm / Q000378:metabolism; D004789:Enzyme Activation / Q000502:physiology; D006367:HeLa Cells; D006801:Humans; D064799:Hypoxia-Inducible Factor-Proline Dioxygenases; D009361:Neoplasm Invasiveness; D009369:Neoplasms / Q000378:metabolism / Q000473:pathology*; D010641:Phenotype; D011393:Procollagen-Proline Dioxygenase / Q000378:metabolism*; D021381:Protein Transport / Q000502:physiology; D014407:Tumor Cells, Cultured
C490190:EGLN1 protein, human; D011393:Procollagen-Proline Dioxygenase; D064799:Hypoxia-Inducible Factor-Proline Dioxygenases