Histone deacetylase 8 is deregulated in urothelial cancer but not a target for efficient treatment
Open accessAbstract
BACKGROUND: Previous studies have shown that class-I histone deacetylase (HDAC) 8 mRNA is upregulated in urothelial cancer tissues and urothelial cancer cell lines compared to benign controls. Using urothelial cancer cell lines we evaluated whether specific targeting of HDAC8 might be a therapeutic option in bladder cancer treatment. METHODS: We conducted siRNA-mediated knockdown and specific pharmacological inhibition of HDAC8 with the three different inhibitors compound 2, compound 5, and compound 6 in several urothelial carcinoma cell lines with distinct HDAC8 expression profiles. Levels of HDAC and marker proteins were determined by western blot analysis and mRNA levels were measured by quantitative real-time PCR. Cellular effects of HDAC8 suppression were analyzed by ATP assay, flow cytometry, colony forming assay and migration assay. RESULTS: Efficient siRNA-mediated knockdown of HDAC8 reduced proliferation up to 45%. The HDAC8 specific inhibitors compound 5 and compound 6 significantly reduced viability of all urothelial cancer cell lines (IC₅₀ 9 - 21 μM). Flow cytometry revealed only a slight increase in the sub-G1 fraction indicating a limited induction of apoptosis. Expression of thymidylate synthase was partly reduced; PARP-cleavage was not detected. The influence of the pharmacological inhibition on clonogenic growth and migration show a cell line- and inhibitor-dependent reduction with the strongest effects after treatment with compound 5 and compound 6. CONCLUSIONS: Deregulation of HDAC8 is frequent in urothelial cancer, but neither specific pharmacological inhibition nor siRNA-mediated knockdown of HDAC8 impaired viability of urothelial cancer cell lines in a therapeutic useful manner. Accordingly, HDAC8 on its own is not a promising drug target in bladder cancer.
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From HDACs and the epigenetic plasticity of cancer cells: target the complexity (2022) · cites this paper as Lehmann et al., 2014
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1 retracted
Roberts, J. T., von der Maase, H., Sengeløv, L., Conte, P., Dogliotti, L., Oliver, R. T. D., Moore, M. J., Zimmermann, A., & Arning, M. (2006) · Annals of Oncology · doi:10.1093/annonc/mdj965 · Cited by 115 · see citing works
RetractedEstimates of worldwide burden of cancer in 2008: GLOBOCAN 2008
Ferlay, J., Shin, H., Bray, F., Forman, D., Mathers, C. D., & Parkin, D. M. (2010) · International Journal of Cancer · doi:10.1002/ijc.25516 · Cited by 21,271 · see citing works
Nicoletti, I., Migliorati, G., Pagliacci, M. C., Grignani, F., & Riccardi, C. (1991) · Journal of Immunological Methods · doi:10.1016/0022-1759(91)90198-o · Cited by 4,580 · see citing works
Lysine acetylation targets protein complexes and co-regulates major cellular functions
Choudhary, C., Kumar, C., Gnad, F., Nielsen, M. L., Rehman, M., Walther, T. C., Olsen, J. V., & Mann, M. (2009) · Science · doi:10.1126/science.1175371 · Cited by 4,040 · see citing works
Cancer epigenetics: from mechanism to therapy
Dawson, M. A., & Kouzarides, T. (2012) · Cell · doi:10.1016/j.cell.2012.06.013 · Cited by 3,203 · see citing works
Histone deacetylases (HDACs): characterization of the classical HDAC family
RUIJTER, A. J. M. D., GENNIP, A. H. V., CARON, H. N., KEMP, S., & KUILENBURG, A. B. P. V. (2003) · Biochemical Journal · doi:10.1042/bj20021321 · Cited by 3,114 · see citing works
Histone acetylation in chromatin structure and transcription
Grunstein, M. (1997) · Nature · doi:10.1038/38664 · Cited by 2,884 · see citing works
Activation of p53 Sequence-Specific DNA Binding by Acetylation of the p53 C-Terminal Domain
Gu, W., & Roeder, R. G. (1997) · Cell · doi:10.1016/s0092-8674(00)80521-8 · Cited by 2,559 · see citing works
Histone deacetylases and cancer: causes and therapies
Marks, P. A., Rifkind, R. A., Richon, V. M., Breslow, R., Miller, T., & Kelly, W. K. (2001) · Nature reviews. Cancer · doi:10.1038/35106079 · Cited by 1,866 · see citing works
Gregoretti, I., Lee, Y.-M., & Goodson, H. V. (2004) · Journal of Molecular Biology · doi:10.1016/j.jmb.2004.02.006 · Cited by 1,456 · see citing works
The Rpd3/Hda1 family of lysine deacetylases: from bacteria and yeast to mice and men
Yang, X., & Seto, E. (2008) · Nature Reviews Molecular Cell Biology · doi:10.1038/nrm2346 · Cited by 1,239 · see citing works
HDAC family: What are the cancer relevant targets?
Witt, O., Deubzer, H. E., Milde, T., & Oehme, I. (2009) · Cancer Letters · doi:10.1016/j.canlet.2008.08.016 · Cited by 1,069 · see citing works
Extraction, purification and analysis of histones
Shechter, D., Dormann, H. L., Allis, C. D., & Hake, S. B. (2007) · Nature Protocols · doi:10.1038/nprot.2007.202 · Cited by 1,054 · see citing works
EAU Guidelines on Muscle-invasive and Metastatic Bladder Cancer: Summary of the 2013 Guidelines
Witjes, J. A., Compérat, É., Cowan, N. C., Santis, M. D., Gakis, G., Lebrét, T., Ribal, M. J., van der Heijden, A. G., & Sherif, A. M. (2013) · European Urology · doi:10.1016/j.eururo.2013.11.046 · Cited by 999 · see citing works
Frequent mutations of chromatin remodeling genes in transitional cell carcinoma of the bladder
Gui, Y., Guo, G., Huang, Y., Hu, X., Tang, A., Gao, S., Wu, R., Chen, C., Li, X., Zhou, L., et al. (2011) · Nature Genetics · doi:10.1038/ng.907 · Cited by 748 · see citing works
Vannini, A., Volpari, C., Filocamo, G., Casavola, E. C., Brunetti, M., Renzoni, D., Chakravarty, P., Paolini, C., De Francesco, R., Gallinari, P., et al. (2004) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.0404603101 · Cited by 638 · see citing works
Eco1-Dependent Cohesin Acetylation During Establishment of Sister Chromatid Cohesion
Ben-Shahar, T. R., Heeger, S., Lehane, C., East, P., Flynn, H. R., Skehel, M. J., & Uhlmann, F. (2008) · Science · doi:10.1126/science.1157774 · Cited by 498 · see citing works
Weichert, W., Roske, A.-E., Gekeler, V., Beckers, T. L., Stephan, C., Jung, K., Fritzsche, F., Niesporek, S., Denkert, C., Dietel, M., et al. (2008) · British Journal of Cancer · doi:10.1038/sj.bjc.6604199 · Cited by 478 · see citing works
Balasubramanian, S., Ramos, J., Luo, W., Sirisawad, M., Verner, E., & Buggy, J. J. (2008) · Leukemia · doi:10.1038/leu.2008.9 · Cited by 458 · see citing works
Histone deacetylase 8 in neuroblastoma tumorigenesis
Oehme, I., Deubzer, H. E., Wegener, D., Pickert, D., Linke, J.-P., Hero, B., Kopp-Schneider, A., Westermann, F., Ulrich, S. M., von Deimling, A., et al. (2009) · Clinical Cancer Research · doi:10.1158/1078-0432.ccr-08-0684 · Cited by 398 · see citing works
Self-citationHDAC6, at the crossroads between cytoskeleton and cell signaling by acetylation and ubiquitination
Boyault, C., Sadoul, K., Pabion, M., & Khochbin, S. (2007) · Oncogene · doi:10.1038/sj.onc.1210614 · Cited by 397 · see citing works
Weichert, W., Roske, A.-E., Gekeler, V., Beckers, T. L., Ebert, M. P., Pross, M., Dietel, M., Denkert, C., & Röcken, C. (2008) · The Lancet Oncology · doi:10.1016/s1470-2045(08)70004-4 · Cited by 361 · see citing works
Histone deacetylase 6 plays a role as a distinct regulator of diverse cellular processes
Li, Y., Shin, D., & Kwon, S. H. (2012) · FEBS Journal · doi:10.1111/febs.12079 · Cited by 346 · see citing works
Expression profile of class I histone deacetylases in human cancer tissues
Nakagawa, M., Oda, Y., Eguchi, T., Aishima, S.-I., Yao, T., Hosoi, F., Basaki, Y., Ono, M., Kuwano, M., Tanaka, M., et al. (2007) · Oncology Reports · doi:10.3892/or.18.4.769 · Cited by 343 · see citing works
Lee, J., Leem, S.-H., Lee, S.-Y., Kim, S.-C., Park, E.-S., Kim, S.-B., Kim, S., Kim, Y., Kim, W., & Chu, I. (2010) · Journal of Clinical Oncology · doi:10.1200/jco.2009.25.0977 · Cited by 343 · see citing works
Hu, E., Chen, Z., Fredrickson, T., Zhu, Y., Kirkpatrick, R., Zhang, G.-F., Johanson, K., Sung, C.-M., Liu, R., & Winkler, J. (2000) · Journal of Biological Chemistry · doi:10.1074/jbc.m908988199 · Cited by 309 · see citing works
Histone deacetylase inhibitors (HDACIs): multitargeted anticancer agents
Licciardi, P. V., Ververis, Hiong, & Karagiannis, T. C. (2013) · Biologics · doi:10.2147/btt.s29965 · Cited by 278 · see citing works
Cloning and characterization of a novel human histone deacetylase, HDAC8
BUGGY, J. J., SIDERIS, M. L., MAK, P., LORIMER, D. D., MCINTOSH, B., & CLARK, J. M. (2000) · Biochemical Journal · doi:10.1042/bj3500199 · Cited by 197 · see citing works
Design and evaluation of ‘Linkerless’ hydroxamic acids as selective HDAC8 inhibitors
KrennHrubec, K., Marshall, B. L., Hedglin, M., Verdin, E. M., & Ulrich, S. M. (2007) · Bioorganic & Medicinal Chemistry Letters · doi:10.1016/j.bmcl.2007.02.064 · Cited by 195 · see citing works
Self-citationHistone deacetylases 1, 6 and 8 are critical for invasion in breast cancer
Park, C. (2011) · Oncology Reports · doi:10.3892/or.2011.1236 · Cited by 184 · see citing works
Weichert, W., Denkert, C., Noske, A., et al. (2008) · Neoplasia · doi:10.1593/neo.08474 · Cited by 181 · see citing works
Sternberg, C. N., Joaquim Bellmunt, B., Sonpavde, G., Siefker-Radtke, A. O., Stadler, W. M., Bajorin, D. F., Dreicer, R., George, D. J., Milowsky, M. I., Theodorescu, D., et al. (2012) · European Urology · doi:10.1016/j.eururo.2012.08.010 · Cited by 170 · see citing works
Negative regulation of histone deacetylase 8 activity by cyclic AMP-dependent protein kinase A
Lee, H., Rezai-Zadeh, N., & Seto, E. (2004) · Molecular and Cellular Biology · doi:10.1128/mcb.24.2.765-773.2004 · Cited by 153 · see citing works
Cloning and characterization of human histone deacetylase 8
Van den Wyngaert, I., de Vries, W., Kremer, A., Neefs, J.-M., Verhasselt, P., Luyten, W. H. M. L., & Kass, S. U. (2000) · FEBS Letters · doi:10.1016/s0014-5793(00)01813-5 · Cited by 143 · see citing works
Waltregny, D., de Leval, L., Glénisson, W., Tran, S. L., North, B. J., Bellahcène, A., Weidle, U. H., Verdin, E. M., & Castronovo, V. (2004) · American Journal Of Pathology · doi:10.1016/s0002-9440(10)63320-2 · Cited by 131 · see citing works
Histone-Modifying Enzymes: Regulators of Developmental Decisions and Drivers of Human Disease
Napierala, J. S., Koutelou, E., Schibler, A. C., & Dent, S. (2012) · Epigenomics · doi:10.2217/epi.12.3 · Cited by 107 · see citing works
Wu, J., Du, C., Lv, Z., Ding, C., Cheng, J., Xie, H., Zhou, L., & Zheng, S. (2013) · Digestive Diseases and Sciences · doi:10.1007/s10620-013-2867-7 · Cited by 103 · see citing works
Lee, H., Sengupta, N., Villagra, A., Rezai‐Zadeh, N., & Seto, E. (2006) · Molecular and Cellular Biology · doi:10.1128/mcb.01971-05 · Cited by 86 · see citing works
Niegisch, G., Knievel, J., Koch, A., Hader, C., Fischer, U., Albers, P., & Schulz, W. A. (2012) · Urologic Oncology Seminars and Original Investigations · doi:10.1016/j.urolonc.2012.06.015 · Cited by 75 · see citing works
Self-citationActivities of MAP-Kinase Pathways in Normal Uroepithelial Cells and Urothelial Carcinoma Cell Lines
Swiatkowski, S. (2002) · Experimental Cell Research · doi:10.1006/excr.2002.5647 · Cited by 73 · see citing works
The biology of lysine acetylation integrates transcriptional programming and metabolism
Patel, J. A., Pathak, R. R., & Mujtaba, S. (2011) · Nutrition & Metabolism · doi:10.1186/1743-7075-8-12 · Cited by 72 · see citing works
Waltregny, D., North, B. J., Mellaert, F. V., de Leval, J., Verdin, E. M., & CASTRONOVO, V. (2004) · PubMed · doi:10.4081/897 · Cited by 71 · see citing works
Yagi, Y., Fushida, S., Harada, S., Kinoshita, J., Makino, I., Oyama, K., Tajima, H., Fujita, H., Takamura, H., Ninomiya, I., et al. (2010) · Journal of Experimental & Clinical Cancer Research · doi:10.1186/1756-9966-29-149 · Cited by 53 · see citing works
Valente, S., & Mai, A. (2014) · Expert Opinion on Therapeutic Patents · doi:10.1517/13543776.2014.877446 · Cited by 48 · see citing works
Limited efficacy of specific HDAC6 inhibition in urothelial cancer cells
Rosik, L., Niegisch, G., Fischer, U., Jung, M., Schulz, W. A., & Hoffmann, M. J. (2014) · Cancer Biology & Therapy · doi:10.4161/cbt.28469 · Cited by 47 · see citing works
Self-citationQuan, P., Moinfar, F., Kufferath, I., et al. (2014) · PubMed · Cited by 29 · see citing works
Ahmad, M., Hamid, A., Hussain, A., Majeed, R., Qurishi, Y., Bhat, J. A., Najar, R. A., Qazi, A. K., Zargar, M. A., Singh, S. K., et al. (2012) · DNA and Cell Biology · doi:10.1089/dna.2011.1575 · Cited by 27 · see citing works
Nichtinvasives und invasives Harnblasenkarzinom
Goebell, P. J., Dorp, F. V., Rödel, C., et al. (2006) · Der Urologe · doi:10.1007/s00120-006-1065-z · Cited by 9 · see citing works
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HDAC8: a multifaceted target for therapeutic interventions
Chakrabarti, A., Oehme, I., Witt, O., Oliveira, G., Sippl, W., Romier, C., Pierce, R. J., & Jung, M. (2015) · Trends in Pharmacological Sciences · doi:10.1016/j.tips.2015.04.013 · Cited by 284 · see citing works
Targeting Histone Deacetylase 8 as a Therapeutic Approach to Cancer and Neurodegenerative Diseases
Chakrabarti, A., Melesina, J., Kolbinger, F. R., Oehme, I., Senger, J., Witt, O., Sippl, W., & Jung, M. (2016) · Future Medicinal Chemistry · doi:10.4155/fmc-2016-0117 · Cited by 111 · see citing works
Zhou, H., Cai, Y., Liu, D., Li, M., Sha, Y., Zhang, W., Wang, K., Gong, J., Tang, N., Huang, A., et al. (2018) · Cell Proliferation · doi:10.1111/cpr.12447 · Cited by 85 · see citing works
HDACs and the epigenetic plasticity of cancer cells: target the complexity
Brancolini, C., Gagliano, T., & Minisini, M. (2022) · Pharmacology & Therapeutics · doi:10.1016/j.pharmthera.2022.108190 · Cited by 55 · see citing works
Hoffmann, M. J., Meneceur, S., Hommel, K., Schulz, W. A., & Niegisch, G. (2021) · Genes · doi:10.3390/genes12020260 · Cited by 28 · see citing works
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- Authors
- Lehmann, M., Hoffmann, M. J., Koch, A., Ulrich, S. M., Schulz, W. A., & Niegisch, G.
- Affiliations
- Heinrich Heine University Düsseldorf (DE)
- Ithaca College (US)
- Corresponding author
- Niegisch, Günter
- Venue
- Journal of Experimental & Clinical Cancer Research
- Published
- 2014-07-10
- Volume
- 33
- Issue
- 1
- Pages
- 59-59
- ISSN
- 0392-9078 (ISSN-L)
- 1756-9966
- PMC
- PMC4230422
- OpenAlex
- W2112157669
- Cited by
- 34
- References
- 48
- Citations by year
- 2025: 1 · 2024: 4 · 2023: 1 · 2022: 2 · 2021: 1 · 2020: 2 · 2019: 6 · 2018: 5 · 2017: 2 · 2016: 5 · 2015: 5
- FWCI
- 1.64
- Type
- journal article
- Language
- en
- Open access
- gold
- doi.org
- Locations
- Journal of Experimental & Clinical Cancer Research (publishedVersion, cc-by)
- Europe PMC (PubMed Central) (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Digital Collections - Ithaca College Library (Ithaca College) (submittedVersion, public-domain)
- Funders
- Deutsche Forschungsgemeinschaft (NI 1398/1-1)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Histone Deacetylase Inhibitors Research
- Health Sciences › Medicine › Surgery › Bladder and Urothelial Cancer Treatments
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Epigenetics and DNA Methylation
- Keywords
- HDAC8, urothelial carcinoma, bladder cancer, histone deacetylase inhibitors, compound 5, compound 6, siRNA knockdown, cell proliferation, apoptosis, thymidylate synthase, cell migration, therapeutic target
- MeSH terms
- Urinary Bladder Neoplasms, Histone Deacetylases, Humans, Hydroxamic Acids, Repressor Proteins, RNA, Small Interfering, Cell Line, Tumor, Gene Knockdown Techniques, Histone Deacetylase Inhibitors, Molecular Targeted Therapy
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