SIRT6通过调控LRP6激活Wnt信号通路促进皮肤癌的机制研究

表观遗传学紊乱在肿瘤的发生发展过程中起重要作用。组蛋白去乙酰化酶SIRT6作为皮肤癌的致癌基因，然而其致癌机理尚不清楚。我们前期发现，SIRT6与LRP6相互作用，增加LRP6蛋白水平，增强LRP6介导的Wnt报告基因活性，提示SIRT6可能通过调节LRP6激活Wnt信号通路。基于此，申请者提出SIRT6通过调控LRP6激活Wnt信号通路促进皮肤癌形成的假说。本项目拟以SIRT6与LRP6相互作用为切入点：生化检测SIRT6通过调控LRP6对Wnt信号通路关键蛋白和靶基因的影响；免疫共沉淀与蛋白印迹鉴定SIRT6与LRP6的相互作用区域、对LRP6的乙酰化及位点；探讨SIRT6调控LRP6表达的分子机理；利用SIRT6转基因小鼠验证SIRT6调控LRP6在化学诱导皮肤癌中的作用。基于上述研究，本项目将从LRP6这个新视点揭示SIRT6促进皮肤癌的发生机制，为皮肤癌的防治提供新思路。

Epigenetic abnormalities play a crucial role in cancer development and progression. SIRT6 is reported as an oncogene in skin cancer, but the mechanisms of SIRT6 on skin tumorigenesis is not clear. Our preliminary data shown that SIRT6 interacted with LRP6 and promoted LRP6 protein expression. SIRT6 elevated TOPFLAH reporter activities activated by LRP6. The results suggested that LRP6 is underlying in SIRT6 activated Wnt signaling pathway. We hypothesize that SIRT6 activated Wnt signaling pathway via regulated LRP6 in skin carcinomas. To clarify the hypothesis, the Wnt related proteins and target genes expression activated by SIRT6 via LRP6 will be determined with reporter system and biochemical detection. The interaction amino acid domain and the acetylation of SIRT6 and LRP6 will be identified with immunoprecipitation and western blotting. The molecular mechanism of SIRT6 in regulating LRP6 protein expression will be explored. Finally, the tumorigenesis of SIRT6 through regulating LRP6 will be confirmed in a two-stage skin carcinogenesis mice model with SIRT6 overexpression. The study will help us in understanding of SIRT6 in skin carcinomas and will provide new clues for skin cancer prevention and therapy.