期刊
CELL
卷 165, 期 6, 页码 1401-1415出版社
CELL PRESS
DOI: 10.1016/j.cell.2016.04.033
关键词
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资金
- NIH [CA175727-01, R21CA198109-01, P50CA1270003, P01 CA117969-07, R01 CA133557-05]
- National Pancreas Foundation
- Linda J. Verville Cancer Research Foundation
- Canadian Institutes of Health Research
- NCI Mentored Clinical Scientist Research Career Development Award [1K08CA194268-01]
- DF/HCC GI SPORE Career Development Project Award [P50CA127003]
- Department of Defense
- Broad Institute SPARC (Scientific Projects to Accelerate Research and Collaboration) program
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.
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