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Updated: Mar 6, 2026
Malachite Green Assay for the Discovery of Heat-Shock Protein 90 Inhibitors
Published on: January 20, 2023
Proteomic analysis of proteome and histone post-translational modifications in heat shock protein 90
Qingdi Quentin Li1, Jian-Jiang Hao2, Zheng Zhang2
1Urologic Oncology Branch, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, Maryland, 20892, USA. liquenti@mail.nih.gov.
Abstract:
Heat shock protein 90 (HSP90) inhibition is an attractive strategy for cancer treatment. Several HSP90 inhibitors have shown promising effects in clinical oncology trials. However, little is known about HSP90 inhibition-mediated bladder cancer therapy. Here, we report a quantitative proteomic study that evaluates alterations in protein expression and histone post-translational modifications (PTMs) in bladder carcinoma in response to HSP90 inhibition. We show that 5 HSP90 inhibitors (AUY922, ganetespib, SNX2112, AT13387, and CUDC305) potently inhibited the proliferation of bladder cancer 5637 cells in a dose- and time-dependent manner. Our proteomic study quantified 518 twofold up-regulated and 811 twofold down-regulated proteins common to both AUY922 and ganetespib treatment. Bioinformatic analyses revealed that those differentially expressed proteins were involved in multiple cellular processes and enzyme-regulated signaling pathways, including chromatin modifications and cell death-associated pathways. Furthermore, quantitative proteome studies identified 14 types of PTMs with 93 marks on the core histones, including 34 novel histone marks of butyrylation, citrullination, 2-hydroxyisobutyrylation, methylation, O-GlcNAcylation, propionylation, and succinylation in AUY922- and ganetespib-treated 5637 cells. Together, this study outlines the association between proteomic changes and histone PTMs in response to HSP90 inhibitor treatment in bladder carcinoma cells, and thus intensifies the understanding of HSP90 inhibition-mediated bladder cancer therapeutics.
Insights
Heat shock protein 90 (HSP90) inhibition effectively reduces bladder cancer cell proliferation. This study reveals key protein expression and novel histone modifications linked to HSP90 inhibitor therapy in bladder carcinoma.
Area of Science:
- Oncology
- Molecular Biology
- Biochemistry
Background:
- Heat shock protein 90 (HSP90) is a validated target in cancer therapy.
- HSP90 inhibitors show promise in clinical trials, but their role in bladder cancer is underexplored.
Purpose of the Study:
- To investigate the effects of HSP90 inhibition on protein expression and histone post-translational modifications (PTMs) in bladder cancer.
- To elucidate the molecular mechanisms underlying HSP90 inhibition-mediated bladder cancer therapy.
Main Methods:
- Quantitative proteomic analysis of bladder cancer 5637 cells treated with HSP90 inhibitors (AUY922, ganetespib, SNX2112, AT13387, CUDC305).
- Bioinformatic analysis of differentially expressed proteins and identified histone PTMs.
Main Results:
- HSP90 inhibitors potently inhibited bladder cancer cell proliferation.
- Proteomic analysis identified significant alterations in protein expression, with 518 proteins upregulated and 811 downregulated.
- Identified 14 types of histone PTMs, including 34 novel marks, associated with HSP90 inhibition.
Conclusions:
- HSP90 inhibition impacts diverse cellular processes, including chromatin modification and cell death pathways in bladder cancer.
- This study provides insights into the proteomic and epigenetic changes induced by HSP90 inhibitors, enhancing understanding of their therapeutic potential in bladder carcinoma.
