Extracellular Hsp90 as a Novel Epigenetic of EMT and Metastatic Risk in Prostate Cancer
Technical Report,30 Sep 2012,29 Sep 2015
Medical University of South Carolina Charleston United States
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Although tumor cells preferentially secrete Hsp90, the function of this extracellular Hsp90 eHsp90 is not well understood. Our work provides novel mechanistic insights into its oncogenic action within the context of prostate cancer. Our findings indicate that eHsp90 serves as a rheostat for ERK-MAPK activity, which subsequently up regulates expression of the oncogenic polycomb methyltransferase EZH2. Moreover, an eHsp90-ERK axis directed EZH2 recruitment to the promoters of target genes, eliciting the suppression of the EMT gatekeeper Ecadherin. Moreover, EZH2 activity was critical for maintaining expression of EMT drivers such as Snail and Zeb, indicating that eHsp90-EZH2 signaling broadly orchestrates molecular changes known to support tumor progression. Our newer findings indicate that ERK-MAPK signaling may also modulate EZH2 recruitment to EMT effector targets. Moreover, HDAC12 differentially recruits EZH2 to the E-cadherin promoter. Finally, we show that, although eHsp90 promotes a stem-like phenotype, ERK and EZH2 activity regulate discrete components of this pathway. Interestingly, EZH2 blockade is less efficacious after formation and propagation of stem-like cells, indicating potential clinical roadblocks for tumor treatment. Overall, we demonstrate that an eHsp90-EZH2oncogenic pathway supports EMT activation and cellular de-differentiation, events that are collectively predicted to promote cancer progression and treatment resistance.