Novel function of molecular chaperone HSP70: suppression of oncogenic FOXM1 after proteotoxic stress [Gene Regulation]

November 11th, 2015 by Halasi, M., Varalȷai, R., Benevolenskaya, E., Gartel, A. L.

Oncogenic transcription factor FOXM1 is overexpressed in the majority of human cancers and it is a potential target for anticancer drugs. We identified proteasome inhibitors as the first type of drugs that target FOXM1 in cancer cells. Here, we found that HSP90 inhibitor PF-4942847 and heat shock also suppress FOXM1. The common effector, which was induced after treatment with proteasome and HSP90 inhibitors or heat-shock, was the molecular chaperone HSP70. We show that HSP70 binds to FOXM1 following proteotoxic stress and that HSP70 inhibits FOXM1 DNA- binding ability. Inhibition of FOXM1 transcriptional auto-regulation by HSP70 leads to the suppression of FOXM1 protein expression. In addition, HSP70 suppression elevates FOXM1 expression and simultaneous inhibition of FOXM1 and HSP70 increases the sensitivity of human cancer cells to anticancer drug-induced apoptosis. Overall, we determined the unique and novel mechanism of FOXM1 suppression by proteasome inhibitors.