Ming Mei, Han Weinong, Zhao Baozhong, Sundaresan Nagalingam R, Deng Chu-Xia, Gupta Mahesh P, He Yu-Ying
Department of Medicine, Section of Dermatology, University of Chicago, Chicago, Illinois.
Department of Surgery, Committee on Cellular and Molecular Physiology, University of Chicago, Chicago, Illinois. Division of Biological Sciences, Department of Microbiology and Cell Biology, Indian Institute of Science, Bangalore, Karnataka, India.
Cancer Res. 2014 Oct 15;74(20):5925-33. doi: 10.1158/0008-5472.CAN-14-1308.
SIRT6 is a SIR2 family member that regulates multiple molecular pathways involved in metabolism, genomic stability, and aging. It has been proposed previously that SIRT6 is a tumor suppressor in cancer. Here, we challenge this concept by presenting evidence that skin-specific deletion of SIRT6 in the mouse inhibits skin tumorigenesis. SIRT6 promoted expression of COX-2 by repressing AMPK signaling, thereby increasing cell proliferation and survival in the skin epidermis. SIRT6 expression in skin keratinocytes was increased by exposure to UVB light through activation of the AKT pathway. Clinically, we found that SIRT6 was upregulated in human skin squamous cell carcinoma. Taken together, our results provide evidence that SIRT6 functions as an oncogene in the epidermis and suggest greater complexity to its role in epithelial carcinogenesis.
SIRT6是SIR2家族成员，可调节参与代谢、基因组稳定性和衰老的多种分子途径。先前有人提出SIRT6是癌症中的肿瘤抑制因子。在此，我们通过提供证据表明小鼠皮肤特异性缺失SIRT6可抑制皮肤肿瘤发生，对这一概念提出了挑战。SIRT6通过抑制AMPK信号促进COX-2的表达，从而增加皮肤表皮中的细胞增殖和存活。通过激活AKT途径暴露于UVB光下可增加皮肤角质形成细胞中SIRT6的表达。临床上，我们发现SIRT6在人类皮肤鳞状细胞癌中上调。综上所述，我们的结果提供了证据表明SIRT6在表皮中作为癌基因发挥作用，并提示其在上皮癌发生中的作用具有更大的复杂性。
