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Updated: Aug 6, 2026
Assays for Validating Histone Acetyltransferase Inhibitors
Published on: August 6, 2020
Radiosensitization of colorectal carcinoma cell lines by histone deacetylase inhibition
Kjersti Flatmark1, Ragnhild V Nome, Sigurd Folkvord
1Department of Tumor Biology, Rikshospitalet-Radiumhospitalet Medical Center, University of Oslo, 0310 Oslo, Norway. kjersti.flatmark@labmed.uio.no
Background:
The tumor response to preoperative radiotherapy of locally advanced rectal cancer varies greatly, warranting the use of experimental models to assay the efficacy of molecular targeting agents in rectal cancer radiosensitization. Histone deacetylase (HDAC) inhibitors, agents that cause hyperacetylation of histone proteins and thereby remodeling of chromatin structure, may override cell cycle checkpoint responses to DNA damage and amplify radiation-induced tumor cell death.
Methods:
Human colorectal carcinoma cell lines were exposed to ionizing radiation and HDAC inhibitors, and cell cycle profiles and regulatory factors, as well as clonogenicity, were analyzed.
Results:
In addition to G(2)/M phase arrest following irradiation, the cell lines displayed cell cycle responses typical for either intact or defective p53 function (the presence or absence, respectively, of radiation-induced expression of the cell cycle inhibitor p21 and subsequent accumulation of G(1) phase cells). In contrast, histone acetylation was associated with complete depletion of the G1 population of cells with functional p53 but accumulation of both G(1) and G(2)/M populations of cells with defective p53. The cellular phenotypes upon HDAC inhibition were consistent with the observed repression of Polo-like kinase-1, a regulatory G(2)/M phase kinase. Following pre-treatment with HDAC inhibitors currently undergoing clinical investigation, the inhibitory effect of ionizing radiation on clonogenicity was significantly amplified.
Conclusion:
In these experimental models, HDAC inhibition sensitized the tumor cells to ionizing radiation, which is in accordance with the concept of increased probability of tumor cell death when chromatin structure is modified.
Insights
Histone deacetylase (HDAC) inhibitors enhance rectal cancer cell radiosensitivity by modifying chromatin structure. This radiosensitization amplifies tumor cell death when combined with ionizing radiation therapy.
Area of Science:
- Oncology
- Molecular Biology
- Radiotherapy
Background:
- Tumor response to preoperative radiotherapy in rectal cancer is highly variable.
- Experimental models are crucial for evaluating molecular targeting agents in radiosensitization.
- Histone deacetylase (HDAC) inhibitors remodel chromatin structure, potentially enhancing radiation-induced cell death.
Purpose of the Study:
- To investigate the efficacy of HDAC inhibitors in sensitizing rectal cancer cells to ionizing radiation.
- To analyze the impact of HDAC inhibition on cell cycle regulation and clonogenicity following irradiation.
Main Methods:
- Human colorectal carcinoma cell lines were treated with ionizing radiation and HDAC inhibitors.
- Cell cycle profiles, regulatory factors (including p53 and p21), and clonogenicity were assessed.
- The role of Polo-like kinase-1 in response to HDAC inhibition was examined.
Main Results:
- HDAC inhibition altered cell cycle progression, causing G1 population depletion in p53-functional cells and G1/G2/M accumulation in p53-defective cells.
- HDAC inhibitors repressed Polo-like kinase-1, a key regulator of the G2/M phase.
- Pre-treatment with HDAC inhibitors significantly amplified the reduction in clonogenicity caused by ionizing radiation.
Conclusions:
- HDAC inhibition effectively sensitizes rectal cancer cells to ionizing radiation in experimental models.
- Modifying chromatin structure via HDAC inhibition increases the probability of tumor cell death when combined with radiotherapy.
