SIRT6 Suppresses Pancreatic Cancer through Control of Lin28b.
SIRT6 Suppresses Pancreatic Cancer through Control of Lin28b.
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DOI：
10.1016/j.cell.2016.04.033
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发表时间：
2016-06-02
期刊：
影响因子：
64.5
通讯作者：
Mostoslavsky R
中科院分区：
文献类型：
--
作者：
Kugel S;Sebastián C;Fitamant J;Ross KN;Saha SK;Jain E;Gladden A;Arora KS;Kato Y;Rivera MN;Ramaswamy S;Sadreyev RI;Goren A;Deshpande V;Bardeesy N;Mostoslavsky R
染色质重塑蛋白在人类癌症中经常失调，但对它们如何控制肿瘤发生知之甚少。在这里，我们发现了一个由NAD+依赖性组蛋白脱乙酰酶Sirtuin 6（SIRT 6）介导的表观遗传程序，该程序对抑制胰腺导管腺癌（PDAC）至关重要，PDAC是最致命的恶性肿瘤之一。SIRT 6失活通过上调Lin 28 b（let-7 microRNA的负调节因子）加速PDAC进展和转移。SIRT 6缺失导致Lin 28 b启动子处的组蛋白超乙酰化、Myc募集以及Lin 28 b和下游let-7靶基因HMGA 2、IGF 2BP 1和IGF 2BP 3的显著诱导。这种表观遗传学程序定义了一个具有不良预后的独特子集，占人类PDAC的30-40%，其特征在于SIRT 6表达降低和肿瘤生长对Lin 28 b的精确依赖。因此，我们确定SIRT 6作为一个重要的PDAC肿瘤抑制因子，并发现Lin 28 b通路作为一个潜在的治疗靶点在分子定义的PDAC子集。
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 with a poor prognosis, representing 30–40% of human PDAC, characterized by reduced SIRT6 expression 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 molecularly-defined PDAC subset.