MUC1 oncoprotein activates the FOXO3a transcription factor in a survival response to oxidative stress

The MUC1 transforming protein is aberrantly overexpressed by most human carcinomas. Recent studies demonstrated that MUC1 confers a protective function against oxidative stress-induced apoptosis; however, the mechanisms responsible for this response are not known. The present work demonstrates that MUC1 regulates FKHRL1/FOXO3a, a member of the forkhead family of transcription factors that induces oxidant scavenging and DNA repair. We show that MUC1 attenuates activation of the phosphoinositide 3-kinase --> phospho-Akt/PKB pathway in HCT116 colon carcinoma cells and thereby decreases FOXO3a phosphorylation. MUC1 is expressed as an N-terminal ectodomain that is tethered to the cell surface by a C-terminal transmembrane subunit. The results demonstrate that the MUC1 cytoplasmic domain is sufficient to induce FOXO3a activation and attenuation of oxidative stress. We also demonstrate that stable down-regulation of endogenous MUC1 in ZR-75-1 breast cancer cells inactivates FOXO3a, increases intracellular oxidant levels, and sensitizes cells to H(2)O(2)-induced necrosis. These findings indicate that MUC1 regulates the FOXO3a signaling pathway in a survival response to oxidative stress.