Molecular Cell paper provides evidence that FOXO3a triggers transcription of HIF1 target gene, which in turn inhibits HIF-1 induced apoptosis.

Scientists report that an evolutionarily conserved transcription factor may have both positive and negative effects on tumor growth depending on whether or not the tumor cells have enough oxygen.

Response to hypoxia is primarily mediated by the hypoxia-inducible transcription factors, HIF1 and HIF2. Recent research also revealed an anticancer role for HIF1 that is mediated by the initiation of apoptosis in response to severe hypoxic stress, according to the researchers.

Tak W. Mak, Ph.D., from the Campbell Family Institute for Breast Cancer Research at Princess Margaret Hospital in Toronto, and colleagues found that hypoxia stimulates an HIF1-dependent increase in a protein called FOXO3a. HIF-1 induced apoptosis in normal and breast cancer cells was inhibited due to FOXO3a stimulating the transcription of the HIF1 target gene, CITED2, according to Dr. Mak. Activation of CITED2, known to exert a negative influence on HIF1 activity, thus resulted in reduced expression of proapoptotic HIF1 target genes.

“Our results reveal a pro-survival role for FOXO3a in normal cells and cancer cells that are adapting to hypoxic stress,” explains Dr. Mak. “Targeting of this pathway may benefit cancer treatment. Tumorigenesis could possibly be inhibited by either very high levels of FOXO3a/CITED2 activity that would cause complete inhibition of HIF1 or very low levels that would permit HIF1-induced apoptosis under hypoxic stress.”

The research will appear in the December 28 issue of Molecular Cell.

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