Mutation of the co-chaperone Tsc1 in bladder cancer diminishes Hsp90 acetylation and reduces drug sensitivity and selectivity.

Mark R Woodford,Dimitra Bourboulia,Alexander J Baker-Williams,Mehdi Mollapour,Michael Hughes,Gennady Bratslavsky,Michael Wong,Joseph M Jacob,Rebecca A Sager,Oleg Shapiro,Michael S Bratslavsky,Sarah J Backe

doi:10.18632/oncotarget.27217

Abstract

The molecular chaperone Heat shock protein 90 (Hsp90) is essential for the folding, stability, and activity of several drivers of oncogenesis. Hsp90 inhibitors are currently under clinical evaluation for cancer treatment, however their efficacy is limited by lack of biomarkers to optimize patient selection. We have recently identified the tumor suppressor tuberous sclerosis complex 1 (Tsc1) as a new co-chaperone of Hsp90 that affects Hsp90 binding to its inhibitors. Highly variable mutations of TSC1 have been previously identified in bladder cancer and correlate with sensitivity to the Hsp90 inhibitors. Here we showed loss of TSC1 leads to hypoacetylation of Hsp90-K407/K419 and subsequent decreased binding to the Hsp90 inhibitor ganetespib. Pharmacologic inhibition of histone deacetylases (HDACs) restores acetylation of Hsp90 and sensitizes Tsc1-mutant bladder cancer cells to ganetespib, resulting in apoptosis. Our findings suggest that TSC1 status may predict response to Hsp90 inhibitors in patients with bladder cancer, and co-targeting HDACs can sensitize tumors with Tsc1 mutations to Hsp90 inhibitors.

Highlights

Over 80,000 people will be diagnosed with bladder cancer and approximately 18,000 patients will die from this disease in the United States in 2019 [1]
Our previous study has shown that the presence of tuberous sclerosis complex 1 (Tsc1) co-chaperone, which interacts with Heat shock protein 90 (Hsp90) through the C-terminus of Tsc1, enhances Hsp90 binding to its inhibitors in cells [17]
We have further demonstrated that presence of Tsc1 facilitates accumulation of fluorescently-tagged Hsp90 inhibitor, BODIPY-ganetespib, in bladder cancer cells after 4 hours of treatment (Figure 1C, 1D; Supplementary Figure 1C–1E)

Summary

Introduction

Over 80,000 people will be diagnosed with bladder cancer and approximately 18,000 patients will die from this disease in the United States in 2019 [1]. Hsp chaperone function is coupled to its ability to bind and hydrolyze ATP [10,11,12]. This ATPase activity provides directionality to the Hsp chaperone cycle, which is tightly regulated by both co-chaperone proteins and posttranslational modifications [13,14,15]. Numerous small molecules have been identified that compete with ATP for binding to the amino-domain of Hsp and inhibit its chaperone function, leading to the degradation of many client proteins involved in tumorigenesis [7]. There are currently 7 Hsp inhibitors in clinical trials (https://www. clinicaltrials.gov/), and there is an urgent need to identify biomarkers to help identify those patients that would respond favorably to treatment with Hsp inhibitors [16]

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Results

Conclusion