SIRT6 suppresses pancreatic cancer through control of Lin28b [ChIP-seq]

Chromatin remodeling proteins are frequently dysregulated in human cancer, yet little is known about how they control tumorigenesis. Here, we uncover an epigenetic program mediated by the NAD+-dependent histone deacetylase Sirtuin 6 (SIRT6) that is critical for suppression of pancreatic ductal adenocarcinoma (PDAC), one of the most lethal malignancies. SIRT6 inactivation accelerates PDAC progression and metastasis via upregulation of Lin28b, a negative regulator of the let-7 microRNA. SIRT6 loss results in histone hyperacetylation at the Lin28b promoter, Myc recruitment, and pronounced induction of Lin28b and downstream let-7 target genes, HMGA2, IGF2BP1 and IGF2BP3. This epigenetic program defines a distinct subset representing 30-40% of human PDAC, characterized by poor prognosis and an exquisite dependence on Lin28b for tumor growth. Thus, we identify SIRT6 as an important PDAC tumor suppressor, and uncover the Lin28b pathway as a potential therapeutic target in a molecularlydefined PDAC subset. ChIP-Seq experiments to examine H3K56ac histone modifications in murine PDAC cells that are Sirt6 wild type (WT), Sirt6 knock-out (KO), and Sirt6 KO cells engineered to express Sirt6 WT (Sirt6 KO + Sirt6 WT Restored).

染色质重塑蛋白在人类癌症中常发生失调，但目前对其调控肿瘤发生的具体机制尚不清楚。本研究揭示了由烟酰胺腺嘌呤二核苷酸（NAD+）依赖的组蛋白去乙酰化酶沉默信息调节因子6（SIRT6）介导的表观遗传程序，该程序对胰腺导管腺癌（PDAC）——一种致死率极高的恶性肿瘤——的抑制至关重要。SIRT6功能失活通过上调Lin28b（let-7微RNA的负调控因子）的表达，加速PDAC的进展与转移。SIRT6缺失会导致Lin28b基因启动子区域组蛋白高度乙酰化、Myc蛋白招募，并显著诱导Lin28b及其下游let-7靶基因HMGA2、IGF2BP1与IGF2BP3的表达。该表观遗传程序界定了一类占人类PDAC 30%~40%的独特亚型，其临床特征为预后不良，且肿瘤生长对Lin28b具有高度依赖性。综上，本研究确定SIRT6为重要的PDAC肿瘤抑制因子，并揭示Lin28b通路可作为分子分型明确的PDAC亚型的潜在治疗靶点。本研究开展了染色质免疫共沉淀测序（ChIP-Seq）实验，以检测Sirt6野生型（WT）、Sirt6敲除型（KO）以及经工程改造恢复表达野生型Sirt6的Sirt6 KO细胞（Sirt6 KO + Sirt6 WT 恢复组）的小鼠PDAC细胞内的H3K56ac组蛋白修饰水平。