FHIT gene expression is repressed by mitogenic signaling through the PI3K/AKT/FOXO pathway.

The Fragile Histidine Triad gene or FHIT functions as tumor suppressor in many epithelial cell types. Although its tumor suppressive mechanism is the subject of intense study, less is known about how FHIT gene expression itself is regulated. Here we show that PI3 kinase and its downstream target AKT suppress FHIT gene expression in response to growth factor stimulation in actively cycling cells. Upon removal of mitogens from the culture environment, FHIT mRNA and protein levels are observed to increase as a result of derepression from these protooncogenic kinases. AKT signaling through the FOXO transcription factors appears to be the basis for FHIT gene regulation. Increases in FHIT gene expression are directly dependent on endogenous FOXO3a in MCF7 breast carcinoma cells as evidenced by experiments with RNAi targeting FOXO transcription factor family members. Thus, this is the first report demonstrating that FHIT gene expression is normally repressed in actively cycling cells through the PI3K/AKT/FOXO3a axis.