Modulating EGFR Signaling by Targeting the Deacetylase HDAC6-Hsp90 Complex in Breast Tumors.

摘要

By facilitating the structural maturation and thereby the stability and activity oncogenic proteins such as ErbB2, the molecular chaperone Hsp90 has emerged as a promising cancer therapeutic target. Toward understanding the regulation of Hsp90 and identifying new therapeutic approach targeting Hsp90 activity we have characterized reversible acetylation as a critical mechanism that regulates Hsp90 function. Here we present evidence that Hsp90 chaperone activity is regulated by reversible acetylation and controlled by the deacetylase HDAC6. Inactivation of HDAC6 leads to Hsp90 hyperacetylation its dissociation from an essential co-chaperone p23 and a loss of chaperone activity. Using glucocorticoid receptor (GR) as a model client protein we showed that in HDAC6 deficient cells Hsp90-dependent maturation of the glucocorticoid receptor (GR) is compromised providing evidence that HDAC6- catalyzed deacetylation is critical for Hsp90 activity. Our study identifies reversible acetylation as a unique mechanism that regulates Hsp90 chaperone complex activity. Based on this observation we are now investigating whether HDAC6-regulated Hsp90 acetylation is also critical for ErbB2-induced tumor transformation.