A gain-of-function mutant p53–HSF1 feed forward circuit governs adaptation of cancer cells to proteotoxic stress

摘要

To overcome proteotoxic stress inherent to malignant transformation, cancer cells induce a range of adaptive mechanisms, with the master transcription factor heat-shock factor 1 (HSF1)-orchestrated response taking center stage. Here we define a novel gain-of-function of mutant p53 (mutp53), whereby mutp53-overexpressing cancer cells acquire superior tolerance to proteotoxic stress. mutp53 via constitutive stimulation of EGFR and ErbB2 signaling hyperactivates the MAPK and PI3K cascades, which induce stabilization and phosphoactivation of HSF1 on Ser326. Moreover, mutp53 protein via direct interaction with activated p-Ser326 HSF1 facilitates HSF1 recruitment to its specific DNA-binding elements and stimulates transcription of heat-shock proteins including Hsp90. In turn, induced Hsp90 stabilizes its oncogenic clients including EGFR, ErbB2 and mutp53, thereby further reinforcing oncogenic signaling. Thus, mutp53 initiates a feed forward loop that renders cancer cells more resistant to adverse conditions, providing a strong survival advantage.