HDAC turnover, CtIP acetylation and dysregulated DNA damage signaling in colon cancer cells treated with sulforaphane and related dietary isothiocyanates
Rajendran P, Kidane AI, Yu TW, Dashwood WM, Bisson WH, Löhr CV, Ho E, Williams DE, Dashwood RH
Epigenetics · 94 citations
Review labels
Neutral facts our review recorded about how this study was done. They describe method, never whether we like the result.
How it was studied
- Design
- In vitro/mechanistic study (classified by our AI screen)
- Studied in
- Cells or lab samples
- Main outcome
- Mechanisms only
Who paid for it
- Funding
- Independent funding
- Government
- National Institutes of Health
- Government
- National Cancer Institute
- Government
- National Institute of Environmental Health Sciences
- Government
- NCI NIH HHS
- Government
- NIEHS NIH HHS
- Grants
- National Cancer Institute (R01 CA-122906); National Cancer Institute (CA-80176); National Institute of Environmental Health Sciences (ES-00-210); National Cancer Institute (R29 CA065525); National Cancer Institute (CA 090890); National Institute of Environmental Health Sciences (P30ES000210); National Cancer Institute (CA-65525); National Cancer Institute (R01 CA080176); National Cancer Institute (R01 CA065525); National Cancer Institute (P01 CA090890); National Cancer Institute (R01 CA122959); National Cancer Institute (CA122959); National Cancer Institute (CA122906)
Based on 5 listed funder(s) and full-text disclosure statement.
Publication
- Published
- 2013-06-01 · Epigenetics · vol. 8 · issue 6 · pp. 612–623
- Publisher
- Landes Bioscience
- Cited
- 120 citations · more than 97% of similar papers · 6.0× the field average
- Impact
- Top 10% most cited in its field
- References
- 49 works
- Access
- Open access (hybrid journal) · CC-BY-NC
- Research areas
- Genomics, phytochemicals, and oxidative stress · Histone Deacetylase Inhibitors Research · Epigenetics and DNA Methylation
- Keywords
- DNA damage, Biology, Acetylation, Histone, Cancer research, Proteostasis, DNA repair, Histone Acetyltransferases, Cancer cell, Cell biology, Biochemistry, Cancer, DNA, Genetics
- MeSH
- colon, cell line, cell line, tumor, humans, colonic neoplasms, dna damage, isothiocyanates, sulfoxides, histone deacetylases, endodeoxyribonucleases, carrier proteins, nuclear proteins, antineoplastic agents, apoptosis, gene expression, acetylation, autophagy, histone deacetylase inhibitors, cell cycle checkpoints
9 authors
From US, NO
- Praveen Rajendran · correspondingOregon State University; Oregon University System; Corvallis Environmental Center; Linus (Norway)
- Ariam I. KidaneOregon State University; Oregon University System; Corvallis Environmental Center; Linus (Norway)
- Tianwei YuOregon State University; Oregon University System; Corvallis Environmental Center; Linus (Norway)
- Wan‐Mohaiza DashwoodOregon State University; Oregon University System; Corvallis Environmental Center; Linus (Norway)
- William H. BissonOregon State University; Corvallis Environmental Center
- Christiane V. LöhrOregon State University; Corvallis Environmental Center
Abstract
Histone deacetylases (HDACs) and acetyltransferases have important roles in the regulation of protein acetylation, chromatin dynamics and the DNA damage response. Here, we show in human colon cancer cells that dietary isothiocyanates (ITCs) inhibit HDAC activity and increase HDAC protein turnover with the potency proportional to alkyl chain length, i.e., AITC < sulforaphane (SFN) < 6-SFN < 9-SFN. Molecular docking studies provided insights into the interactions of ITC metabolites with HDAC3, implicating the allosteric site between HDAC3 and its co-repressor. ITCs induced DNA double-strand breaks and enhanced the phosphorylation of histone H2AX, ataxia telangiectasia and Rad3-related protein (ATR) and checkpoint kinase-2 (CHK2). Depending on the ITC and treatment conditions, phenotypic outcomes included cell growth arrest, autophagy and apoptosis. Coincident with the loss of HDAC3 and HDAC6, as well as SIRT6, ITCs enhanced the acetylation and subsequent degradation of critical repair proteins, such as CtIP, and this was recapitulated in HDAC knockdown experiments. Importantly, colon cancer cells were far more susceptible than non-cancer cells to ITC-induced DNA damage, which persisted in the former case but was scarcely detectable in non-cancer colonic epithelial cells under the same conditions. Future studies will address the mechanistic basis for dietary ITCs preferentially exploiting HDAC turnover mechanisms and faulty DNA repair pathways in colon cancer cells vs. normal cells.
Abstract via Europe PMC. Copyright remains with the authors or publisher (CC BY-NC).
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