Histone deacetylase inhibitor-induced cell death in bladder cancer is associated with chromatin modification and modifying protein expression: A proteomic approach

  • Authors:
    • Qingdi Quentin Li
    • Jian-Jiang Hao
    • Zheng Zhang
    • Iawen Hsu
    • Yi Liu
    • Zhen Tao
    • Keidren Lewi
    • Adam R. Metwalli
    • Piyush K. Agarwal
  • View Affiliations

  • Published online on: April 7, 2016     https://doi.org/10.3892/ijo.2016.3478
  • Pages: 2591-2607
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Abstract

The Cancer Genome Atlas (TCGA) project recently identified the importance of mutations in chromatin remodeling genes in human carcinomas. These findings imply that epigenetic modulators might have a therapeutic role in urothelial cancers. To exploit histone deacetylases (HDACs) as targets for cancer therapy, we investigated the HDAC inhibitors (HDACIs) romidepsin, trichostatin A, and vorinostat as potential chemotherapeutic agents for bladder cancer. We demonstrate that the three HDACIs suppressed cell growth and induced cell death in the bladder cancer cell line 5637. To identify potential mechanisms associated with the anti-proliferative and cytotoxic effects of the HDACIs, we used quantitative proteomics to determine the proteins potentially involved in these processes. Our proteome studies identified a total of 6003 unique proteins. Of these, 2472 proteins were upregulated and 2049 proteins were downregulated in response to HDACI exposure compared to the untreated controls (P<0.05). Bioinformatic analysis further revealed that those differentially expressed proteins were involved in multiple biological functions and enzyme-regulated pathways, including cell cycle progression, apoptosis, autophagy, free radical generation and DNA damage repair. HDACIs also altered the acetylation status of histones and non-histone proteins, as well as the levels of chromatin modification proteins, suggesting that HDACIs exert multiple cytotoxic actions in bladder cancer cells by inhibiting HDAC activity or altering the structure of chromatin. We conclude that HDACIs are effective in the inhibition of cell proliferation and the induction of apoptosis in the 5637 bladder cancer cells through multiple cell death-associated pathways. These observations support the notion that HDACIs provide new therapeutic options for bladder cancer treatment and thus warrant further preclinical exploration.
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June-2016
Volume 48 Issue 6

Print ISSN: 1019-6439
Online ISSN:1791-2423

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Spandidos Publications style
Li QQ, Hao J, Zhang Z, Hsu I, Liu Y, Tao Z, Lewi K, Metwalli AR and Agarwal PK: Histone deacetylase inhibitor-induced cell death in bladder cancer is associated with chromatin modification and modifying protein expression: A proteomic approach. Int J Oncol 48: 2591-2607, 2016
APA
Li, Q.Q., Hao, J., Zhang, Z., Hsu, I., Liu, Y., Tao, Z. ... Agarwal, P.K. (2016). Histone deacetylase inhibitor-induced cell death in bladder cancer is associated with chromatin modification and modifying protein expression: A proteomic approach. International Journal of Oncology, 48, 2591-2607. https://doi.org/10.3892/ijo.2016.3478
MLA
Li, Q. Q., Hao, J., Zhang, Z., Hsu, I., Liu, Y., Tao, Z., Lewi, K., Metwalli, A. R., Agarwal, P. K."Histone deacetylase inhibitor-induced cell death in bladder cancer is associated with chromatin modification and modifying protein expression: A proteomic approach". International Journal of Oncology 48.6 (2016): 2591-2607.
Chicago
Li, Q. Q., Hao, J., Zhang, Z., Hsu, I., Liu, Y., Tao, Z., Lewi, K., Metwalli, A. R., Agarwal, P. K."Histone deacetylase inhibitor-induced cell death in bladder cancer is associated with chromatin modification and modifying protein expression: A proteomic approach". International Journal of Oncology 48, no. 6 (2016): 2591-2607. https://doi.org/10.3892/ijo.2016.3478