HDAC inhibitor confers radiosensitivity to prostate stem-like cells

Frame, F M; Pellacani, D; Collins, A T; Simms, M S; Mann, V M; Jones, GDD; Meuth, M; Bristow, R G; Maitland, N J

Abstract

Background:
Radiotherapy can be an effective treatment for prostate cancer, but radiorecurrent tumours do develop. Considering prostate cancer heterogeneity, we hypothesised that primitive stem-like cells may constitute the radiation-resistant fraction.

Methods:
Primary cultures were derived from patients undergoing resection for prostate cancer or benign prostatic hyperplasia. After short-term culture, three populations of cells were sorted, reflecting the prostate epithelial hierarchy, namely stem-like cells (SCs, α2β1integrinhi/CD133+), transit-amplifying (TA, α2β1integrinhi/CD133−) and committed basal (CB, α2β1integrinlo) cells. Radiosensitivity was measured by colony-forming efficiency (CFE) and DNA damage by comet assay and DNA damage foci quantification. Immunofluorescence and flow cytometry were used to measure heterochromatin. The HDAC (histone deacetylase) inhibitor Trichostatin A was used as a radiosensitiser.

Results:
Stem-like cells had increased CFE post irradiation compared with the more differentiated cells (TA and CB). The SC population sustained fewer lethal double-strand breaks than either TA or CB cells, which correlated with SCs being less proliferative and having increased levels of heterochromatin. Finally, treatment with an HDAC inhibitor sensitised the SCs to radiation.

Interpretation:
Prostate SCs are more radioresistant than more differentiated cell populations. We suggest that the primitive cells survive radiation therapy and that pre-treatment with HDAC inhibitors may sensitise this resistant fraction.

Citation

Frame, F. M., Pellacani, D., Collins, A. T., Simms, M. S., Mann, V. M., Jones, G., Meuth, M., Bristow, R. G., & Maitland, N. J. (2013). HDAC inhibitor confers radiosensitivity to prostate stem-like cells. The British Journal of Cancer, 109(12), 3023-3033. https://doi.org/10.1038/bjc.2013.691

• Journal Article Type: Article
• Acceptance Date: Oct 9, 2013
• Online Publication Date: Nov 12, 2013
• Publication Date: Dec 10, 2013
• Deposit Date: Jun 25, 2019
• Publicly Available Date: Jun 25, 2019
• Journal: British Journal of Cancer
• Print ISSN: 0007-0920
• Electronic ISSN: 1532-1827
• Publisher: Nature Publishing Group
• Peer Reviewed: Peer Reviewed
• Volume: 109
• Issue: 12
• Pages: 3023-3033
• DOI: https://doi.org/10.1038/bjc.2013.691
• Keywords: Cancer Research; Oncology
• Public URL: https://hull-repository.worktribe.com/output/2037387
• Publisher URL: https://www.nature.com/articles/bjc2013691
• Additional Information: From twelve months after its original publication, this work is licensed under the Creative Commons Attribution-NonCommercial-Share Alike 3.0 Unported License. To view a copy of this license, visit http://creativecommons.org/licenses/by-nc-sa/3.0/
• Contract Date: Jun 25, 2019