| Literature DB >> 27180906 |
Sita Kugel1, Carlos Sebastián1, Julien Fitamant1, Kenneth N Ross1, Supriya K Saha1, Esha Jain2, Adrianne Gladden3, Kshitij S Arora4, Yasutaka Kato4, Miguel N Rivera4, Sridhar Ramaswamy1, Ruslan I Sadreyev5, Alon Goren3, Vikram Deshpande4, Nabeel Bardeesy1, Raul Mostoslavsky6.
Abstract
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.Entities:
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Year: 2016 PMID： 27180906 PMCID： PMC4892983 DOI： 10.1016/j.cell.2016.04.033
Source DB: PubMed Journal: Cell ISSN： 0092-8674 Impact factor: 41.582