Abstract
Abstract The protein deacetylase SIRT1, a mammalian counterpart of the yeast silent information regulator 2 (Sir2) and a proto member of the sirtuin family, regulates various pathways in metabolism, DNA repair, and cell survival. However, the role of SIRT1 in cancer is still under debate. Here we show that the role of SIRT1 in skin cancer development induced by the human skin carcinogen UVB radiation is dependent on its gene dose. Keratinocyte-specific heterozygous deletion of SIRT1 increases UVB-induced skin tumorigenesis, whereas homozygous deletion of SIRT1 decreases skin tumorigenesis. In mouse skin, SIRT1 is haploinsufficient for DNA repair and the expression of xeroderma pigmentosum C (XPC), a protein critical for repairing UVB-induced DNA damage. Similar to homozygous SIRT1 deletion, heterozygous SIRT1 deletion reduces the XPC protein levels and UVB-induced DNA damage repair. As compared with normal human skin, down-regulation of SIRT1 is in parallel with down-regulation of XPC in human cutaneous squamous cell carcinoma at both the protein and mRNA levels. In contrast, homozygous SIRT1 deletion in mouse skin augments p53 acetylation, and the expression of its transcriptional target Noxa, and sensitizes epidermis to UVB-induced apoptosis in vivo, while heterozygous SIRT1 deletion has no effect. Although mice with homozygous SIRT1 deletion do not develop tumors, these mice suffer severe sunburn. The gene dose-dependent function of SIRT1 in DNA repair and cell survival is consistent with its role in UVB-induced skin tumorigenesis and injury. Taken together, our results indicate that, depending on the SIRT1 levels, SIRT1 acts as a tumor suppressor and as an oncogene. Citation Format: Mei Ming, Keyoumars Soltani, Christopher R. Shea, Xiaoling Li, Yu-ying He. Keratinocyte-specific deletion in mice reveals gene dose-dependent function of SIRT1 in tumorigenesis. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 1068. doi:10.1158/1538-7445.AM2013-1068
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