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SIRT6 Suppresses Pancreatic Cancer through Control of Lin28b

2016; Cell Press; Volume: 165; Issue: 6 Linguagem: Inglês

10.1016/j.cell.2016.04.033

1097-4172

Sita Kugel, Carlos Sebastián, Julien Fitamant, Kenneth N. Ross, Supriya K. Saha, Esha Jain, Adrianne D. Gladden, Kshitij S. Arora, Yasutaka Kato, Miguel N. Rivera, Sridhar Ramaswamy, Ruslan I. Sadreyev, Alon Goren, Vikram Deshpande, Nabeel Bardeesy, Raúl Mostoslavsky,

Histone Deacetylase Inhibitors Research

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.PaperClip/cms/asset/ef4b06b0-ab24-49e6-9f1c-7326e377c8c9/mmc8.mp3Loading ...(mp3, 5.17 MB) Download audio