Hypoxia restricts cell proliferation and cell cycle progression at the G1/S interface but at least a subpopulation of
carcinoma cells can escape the restriction. In
carcinoma hypoxia may in fact select for cells with enhanced hypoxic survival and increased aggressiveness. The cellular
oxygen sensors HIF
proline hydroxylases (PHDs) adapt the cellular functions to lowered environmental
oxygen tension. PHD3
isoform has shown the strongest hypoxic upregulation among the family members. We detected a strong PHD3
mRNA expression in
tumors of
head and neck squamous cell carcinoma (
HNSCC). The PHD3 expression associated with expression of hypoxic marker gene. Using
siRNA in cell lines derived from
HNSCC we show that specific inhibition of PHD3 expression in
carcinoma cells caused reduced cell survival in
hypoxia. The loss of PHD3, but not that of PHD2, led to marked cell number reduction. Although
caspase-3 was activated at early
hypoxia no induction of apoptosis was detected. However, hypoxic PHD3 inhibition caused a block in cell cycle progression. Cell population in G1 phase was increased and the population in S phase reduced demonstrating a block in G1 to S transition under PHD3 inhibition. In line with this, the level of hyperphosphorylated
retinoblastoma protein Rb was reduced by PHD3 knock-down in
hypoxia. PHD3 loss led to increase in
cyclin-dependent kinase inhibitor p27 expression but not that of p21 or p16. The data demonstrated that increased PHD3 expression under
hypoxia enhances cell cycle progression and survival of
carcinoma cells.