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Updated: Apr 16, 2026
Assays for Validating Histone Acetyltransferase Inhibitors
Published on: August 6, 2020
TRPM2 mediates histone deacetylase inhibition-induced apoptosis in bladder cancer cells
Qi-feng Cao1, Su-bo Qian, Ning Wang
1Department of Urology, Xinhua Hospital, Shanghai Jiao Tong University School of Medicine , Shanghai, China .
Purpose:
Inhibition of histone deacetylase (HDAC) activity results in growth arrest and apoptosis in multiple types of cancer cells. It has been well established that p21 is responsible for HDAC inhibitor (HDACi)-induced growth inhibition, while the mechanism underlying HDACi-elicited apoptosis in bladder cancer cells remains largely unknown.
Methods:
In this study, the apoptotic response to HDACi (trichostatin A and sodium butyrate) with different concentrations was determined by flow cytometry analysis and real-time polymerase chain reaction was conducted to examine the TRPM2 (Transient receptor potential cation channel, subfamily M, member 2) expression change on HDACi treatment. TRPM2 knockdown and overexpression were performed to investigate the role of TRPM2 in HDACi-induced apoptosis. The mechanism of HDACi-elicited upregulation of TRPM2 was studied by chromatin-immunoprecipitation.
Results:
HDACi efficiently induced cell apoptosis and TRPM2 upregulation in a time- and dose-dependent manner in T24 bladder cancer cells. Functional analysis revealed that TRPM2 overexpression promotes apoptosis of T24 cells. Conversely, TRPM2 depletion remarkably antagonized HDACi-induced apoptosis. Furthermore, HDAC inhibition-elicited TRPM2 upregulation is caused by the increase of acetylated H3K9 (H3K9Ac) enrichment in TRPM2 promoter.
Conclusions:
These data suggest that the HDACi-elicited upregulation of TRPM2 expression is required for HDACi-induced apoptosis in bladder cancer cells and that HDACi activated the enrichment of H3K9Ac-represented permissive chromatin in TRPM2 promoter.
Insights
Histone deacetylase inhibitors (HDACi) induce apoptosis in bladder cancer by upregulating the TRPM2 channel. This upregulation, driven by increased H3K9Ac in the TRPM2 promoter, is crucial for HDACi-mediated cancer cell death.
Area of Science:
- Oncology
- Molecular Biology
- Epigenetics
Background:
- Histone deacetylase (HDAC) inhibition triggers cancer cell growth arrest and apoptosis.
- While p21 mediates HDAC inhibitor (HDACi)-induced growth inhibition, the mechanisms of HDACi-induced apoptosis in bladder cancer are not fully understood.
Purpose of the Study:
- To investigate the mechanism of HDAC inhibitor-induced apoptosis in bladder cancer cells.
- To determine the role of Transient Receptor Potential Cation Channel, Subfamily M, Member 2 (TRPM2) in this process.
Main Methods:
- T24 bladder cancer cells were treated with HDACi (trichostatin A, sodium butyrate).
- Apoptosis was assessed via flow cytometry; TRPM2 expression was analyzed using real-time PCR.
- TRPM2 knockdown/overexpression and chromatin-immunoprecipitation were employed to elucidate TRPM2's role and the underlying regulatory mechanism.
Main Results:
- HDACi treatment led to time- and dose-dependent apoptosis and TRPM2 upregulation in T24 cells.
- TRPM2 overexpression enhanced apoptosis, while TRPM2 depletion inhibited HDACi-induced apoptosis.
- HDAC inhibition increased H3K9 acetylation (H3K9Ac) at the TRPM2 promoter, driving its upregulation.
Conclusions:
- TRPM2 upregulation is essential for HDAC inhibitor-induced apoptosis in bladder cancer.
- HDAC inhibition promotes apoptosis by increasing permissive chromatin marks (H3K9Ac) at the TRPM2 promoter.
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