SIRT6 pharmacological inhibition delays skin cancer progression in the squamous cell carcinoma
Sirtuin 6 (SIRT6) includes a critical role in cutaneous Squamous Cell Carcinoma (cSCC): SIRT6 silencing in skin SCC cells has pro-differentiating effects and SIRT6 deletion abrogated DMBA-TPA-caused skin tumorigenesis in rodents. However, SIRT6 functions as tumor suppressor in SCC by enhancing glycolysis in tumor propagating cells. Herein, medicinal modulation of SIRT6 deacetylase activity was investigated in cSCC, with S6 (inhibitor) or MDL-800 (activator). In cSCC cells, S6 recreated the professional-differentiating results of SIRT6 silencing, because the amounts of Keratin 1, Keratin 10 and Loricrin were upregulated when compared with controls. Next, the results of SIRT6 medicinal modulation were evaluated inside a DMBA-TPA-caused cancer of the skin mouse model. Rodents given the inhibitor S6 inside a preventive approach, i.e. at the outset of the promotion stage, presented reduced number and size papillomas, when compared to controls. The epidermal hyperproliferation marker Keratin 6 and also the cSCC marker Keratin 8 were less abundant when SIRT6 was inhibited. In S6-treated lesions, the Epithelial-Mesenchymal Transition (EMT) markers Zeb1 and Vimentin were less expressed when compared with untreated lesions. Inside a therapeutic approach, i.e. treatment beginning after papilloma appearance, the S6 group presented reduced papillomas (number and size), whereas MDL-800-treated rodents displayed a contrary trend. In S6-treated lesions, Keratin 6 and Keratin 8 were less expressed, EMT was less advanced, having a greater E-cadherin/Vimentin ratio, indicating a delayed carcinogenesis when SIRT6 was inhibited. Our results make sure SIRT6 plays a part in skin carcinogenesis and suggest SIRT6 medicinal inhibition like a promising strategy in cSCC.