SIRT1 inhibition restores apoptotic sensitivity in p53-mutated human keratinocytes

Herbert, K. J. , Cook, A. L. and Snow, E. T. (2014) SIRT1 inhibition restores apoptotic sensitivity in p53-mutated human keratinocytes. Toxicology and Applied Pharmacology, 277(3), pp. 288-297. (doi: 10.1016/j.taap.2014.04.001) (PMID:24726431)

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Abstract

Mutations to the p53 gene are common in UV-exposed keratinocytes and contribute to apoptotic resistance in skin cancer. P53-dependent activity is modulated, in part, by a complex, self-limiting feedback loop imposed by miR-34a-mediated regulation of the lysine deacetylase, SIRT1. Expression of numerous microRNAs is dysregulated in squamous and basal cell carcinomas; however the contribution of specific microRNAs to the pathogenesis of skin cancer remains untested. Through use of RNAi, miRNA target site blocking oligonucleotides and small molecule inhibitors, this study explored the influence of p53 mutational status, SIRT1 activity and miR-34a levels on apoptotic sensitivity in primary (NHEK) and p53-mutated (HaCaT) keratinocyte cell lines. SIRT1 and p53 are overexpressed in p53-mutated keratinocytes, whilst miR-34a levels are 90% less in HaCaT cells. HaCaTs have impaired responses to p53/SIRT1/miR-34a axis manipulation which enhanced survival during exposure to the chemotherapeutic agent, camptothecin. Inhibition of SIRT1 activity in this cell line increased p53 acetylation and doubled camptothecin-induced cell death. Our results demonstrate that p53 mutations increase apoptotic resistance in keratinocytes by interfering with miR-34a-mediated regulation of SIRT1 expression. Thus, SIRT1 inhibitors may have a therapeutic potential for overcoming apoptotic resistance during skin cancer treatment.

Item Type:Articles
Status:Published
Refereed:Yes
Glasgow Author(s) Enlighten ID:Herbert, Dr Katharine
Authors: Herbert, K. J., Cook, A. L., and Snow, E. T.
College/School:College of Medical Veterinary and Life Sciences > School of Cancer Sciences
Journal Name:Toxicology and Applied Pharmacology
Publisher:Elsevier
ISSN:0041-008X
ISSN (Online):1096-0333
Published Online:12 April 2014

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