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SIRT1 inhibition restores apoptotic sensitivity in p53-mutated human keratinocytes

Citation

Herbert, KJ and Cook, AL and Snow, ET, SIRT1 inhibition restores apoptotic sensitivity in p53-mutated human keratinocytes, Toxicology and Applied Pharmacology, 277, (3) pp. 288-297. ISSN 0041-008X (2014) [Refereed Article]

Copyright Statement

Copyright 2014 Elsevier Inc.

DOI: doi:10.1016/j.taap.2014.04.001

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 Details

Item Type:Refereed Article
Keywords:SIRT1, miR-34a, p53, keratinocytes
Research Division:Biological Sciences
Research Group:Biochemistry and Cell Biology
Research Field:Cell Development, Proliferation and Death
Objective Division:Expanding Knowledge
Objective Group:Expanding Knowledge
Objective Field:Expanding Knowledge in the Medical and Health Sciences
Author:Herbert, KJ (Ms Katharine Herbert)
Author:Cook, AL (Dr Tony Cook)
Author:Snow, ET (Associate Professor Elizabeth Snow)
ID Code:91229
Year Published:2014
Web of Science® Times Cited:11
Deposited By:Health Sciences A
Deposited On:2014-05-13
Last Modified:2017-11-02
Downloads:0

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