DNA microarray profiling of genes differentially regulated by the histone deacetylase inhibitors vorinostat and LBH589 in colon cancer cell lines
Open accessAbstract
Background: Despite the significant progress made in colon cancer chemotherapy, advanced disease remains largely incurable and novel efficacious chemotherapies are urgently needed. Histone deacetylase inhibitors (HDACi) represent a novel class of agents which have demonstrated promising preclinical activity and are undergoing clinical evaluation in colon cancer. The goal of this study was to identify genes in colon cancer cells that are differentially regulated by two clinically advanced hydroxamic acid HDACi, vorinostat and LBH589 to provide rationale for novel drug combination partners and identify a core set of HDACi-regulated genes. Methods: HCT116 and HT29 colon cancer cells were treated with LBH589 or vorinostat and growth inhibition, acetylation status and apoptosis were analyzed in response to treatment using MTS, Western blotting and flow cytometric analyses. In addition, gene expression was analyzed using the Illumina Human-6 V2 BeadChip array and Ingenuity®Pathway Analysis. Results: Treatment with either vorinostat or LBH589 rapidly induced histone acetylation, cell cycle arrest and inhibited the growth of both HCT116 and HT29 cells. Bioinformatic analysis of the microarray profiling revealed significant similarity in the genes altered in expression following treatment with the two HDACi tested within each cell line. However, analysis of genes that were altered in expression in the HCT116 and HT29 cells revealed cell-line-specific responses to HDACi treatment. In addition a core cassette of 11 genes modulated by both vorinostat and LBH589 were identified in both colon cancer cell lines analyzed. Conclusion: This study identified HDACi-induced alterations in critical genes involved in nucleotide metabolism, angiogenesis, mitosis and cell survival which may represent potential intervention points for novel therapeutic combinations in colon cancer. This information will assist in the identification of novel pathways and targets that are modulated by HDACi, providing much-needed information on HDACi mechanism of action and providing rationale for novel drug combination partners. We identified a core signature of 11 genes which were modulated by both vorinostat and LBH589 in a similar manner in both cell lines. These core genes will assist in the development and validation of a common gene set which may represent a molecular signature of HDAC inhibition in colon cancer.
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The HCT-116 xenograft model was chosen because it represented the highest HDAC6 expression, has intermediate sensitivity to C1A, and has been used extensively as a model for other HDACIs.
“HCT-116 xenograft model was chosen because it represented the highest HDAC6 expression, has intermediate sensitivity to C1A (thus, data are not biased to high sensitivity tumours only) and it has been used extensively as a model for other HDACIs, including genomic and imaging studies (Leyton et al, 2006a; Witter et al, 2008; LaBonte et al, 2009).”
From A novel small molecule hydroxamate preferentially inhibits HDAC6 activity and tumour growth (2013) · cites this paper as LaBonte et al, 2009
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A novel small molecule hydroxamate preferentially inhibits HDAC6 activity and tumour growth
Kaliszczak, M., Trousil, S., Åberg, O., Perumal, M., Nguyen, Q.-D., & Aboagye, E. O. (2013) · British Journal of Cancer · doi:10.1038/bjc.2012.576 · Cited by 66 · see citing works
- Authors
- LaBonte, M. J., Wilson, P. M., Fazzone, W., Groshen, S., Lenz, H.-J., & Ladner, R. D.
- Affiliations
- University of Southern California (US)
- Corresponding author
- Ladner, Robert D
- Venue
- BMC Medical Genomics
- Published
- 2009-11-30
- Volume
- 2
- Issue
- 1
- Pages
- 67-67
- ISSN
- 1755-8794 (ISSN-L)
- PMC
- PMC2799439
- OpenAlex
- W2049793199
- Cited by
- 99
- References
- 67
- Citations by year
- 2026: 2 · 2025: 1 · 2024: 4 · 2023: 5 · 2022: 3 · 2021: 3 · 2020: 5 · 2019: 10 · 2018: 2 · 2017: 1 · 2016: 5 · 2015: 8 · 2014: 8 · 2013: 12 · 2012: 11
- FWCI
- 3.99
- Type
- journal article
- Language
- en
- Open access
- gold
- doi.org
- Licence
- Locations
- BMC Medical Genomics (publishedVersion, cc-by)
- PubMed Central (publishedVersion, cc-by)
- PubMed (publishedVersion)
- DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
- Research Portal (Queen's University Belfast) (submittedVersion)
- Funders
- National Cancer Institute (P30CA014089)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Histone Deacetylase Inhibitors Research
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Epigenetics and DNA Methylation
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Genomics and Chromatin Dynamics
- Keywords
- histone deacetylase inhibitors, vorinostat, panobinostat, colon cancer, gene expression profiling, histone acetylation, cell cycle arrest, apoptosis, HCT116 cells, HT-29 cells, nucleotide metabolism, angiogenesis, mitosis, cell survival
- MeSH terms
- Vorinostat, Panobinostat, Acetylation, Antineoplastic Agents, Cell Cycle, Colonic Neoplasms, Histone Deacetylases, Humans, Hydroxamic Acids, Indoles, Gene Expression Regulation, Neoplastic, Apoptosis, Oligonucleotide Array Sequence Analysis, Gene Expression Profiling, Cell Line, Tumor, Cell Proliferation, Histone Deacetylase Inhibitors
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