SIRT6 suppresses pancreatic cancer through control of Lin28b [miRNA-seq]. Homo sapiens

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. Overall design: Small RNA-Seq experiments for PLKO and shLIN28B (three replicates each) in human Panc3.27 PDAC cells to identify miRNAs modulateed by LIN28B knockdown.

染色质重塑蛋白在人类癌症中常发生失调，但目前对其如何调控肿瘤发生的机制仍知之甚少。本研究揭示了一种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，该程序对抑制胰腺导管腺癌（PDAC）——一种致死率极高的恶性肿瘤——至关重要。SIRT6失活通过上调Lin28b（一种let-7微RNA的负调控因子）加速PDAC的进展与转移。SIRT6缺失会导致Lin28b启动子区域发生组蛋白高度乙酰化，招募Myc蛋白，并显著诱导Lin28b及其下游let-7靶基因HMGA2、IGF2BP1与IGF2BP3的表达。该表观遗传程序定义了一类占人类PDAC 30%~40%的独特亚型，其特征为预后不良，且肿瘤生长对Lin28b具有极强的依赖性。综上，本研究确认SIRT6是一种重要的PDAC抑癌基因，并揭示Lin28b通路可作为一类分子特征明确的PDAC亚型的潜在治疗靶点。实验整体设计：针对人类Panc3.27 PDAC细胞中的PLKO与shLIN28B组（各设置3次生物学重复）开展小RNA测序实验，以鉴定受LIN28B敲降调控的微RNA。