Mutation of the co-chaperone Tsc1 in bladder cancer diminishes Hsp90 acetylation and reduces drug sensitivity and selectivity
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Mark R. Woodford1,2,3,*, Michael Hughes1,3,*, Rebecca A. Sager1,2,3,4,*, Sarah J. Backe1,2,3, Alexander J. Baker-Williams1,2,3, Michael S. Bratslavsky1,3, Joseph M. Jacob1,3, Oleg Shapiro1,3, Michael Wong5,6, Gennady Bratslavsky1,2,3, Dimitra Bourboulia1,2,3 and Mehdi Mollapour1,2,3
1 Department of Urology, SUNY Upstate Medical University Syracuse, NY 13210, USA
2 Department of Biochemistry and Molecular Biology, SUNY Upstate Medical University Syracuse, NY 13210, USA
3 Upstate Cancer Center, SUNY Upstate Medical University Syracuse, NY 13210, USA
4 College of Medicine, SUNY Upstate Medical University Syracuse, NY 13210, USA
5 Department of Neurology, Washington University School of Medicine, Saint Louis, MO 63110, USA
6 Hope Center for Neurological Disorders, Washington University School of Medicine, Saint Louis, MO 63110, USA
* These authors contributed equally to this work
Keywords: tuberous sclerosis complex (TSC); Tsc1 (Hamartin); Tsc2 (Tuberin); heat shock protein (Hsp90); bladder cancer
Received: July 23, 2019 Accepted: August 29, 2019 Published: October 08, 2019
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.
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