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SIRT6 Suppresses Pancreatic Cancer through Control of Lin28b
Open accessAbstract
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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“These findings indicate that molecules that activate sirtuins in humans may not only provide broad health benefits with potent anti-inflammatory, cardio-protective, neuroprotective, and anti-tumor activities (Kugel et al., 2016).”
BackgroundWang, S., Zheng, Y., Yang, F., Zhu, L., Zhu, X.-Q., Wang, Z.-F., Wu, X.-L., Zhou, C.-H., Yan, J.-Y., Hu, B.-Y., et al. (2021) · Signal Transduction and Targeted Therapy · doi:10.1038/s41392-021-00659-4 · Cited by 369
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Metadata
- Authors
- Kugel, S., Sebastián, C., Fitamant, J., Ross, K. N., Saha, S. K., Jain, E., Gladden, A., Arora, K. S., Kato, Y., Rivera, M. N., Ramaswamy, S., Sadreyev, R. I., Goren, A., Deshpande, V., Bardeesy, N., & Mostoslavsky, R.
- Venue
- Cell
- Publisher
- Elsevier BV
- Published
- 2016-06
- Volume
- 165
- Issue
- 6
- Pages
- 1401-1415
- ISSN
- 0092-8674 (ISSN-L)
- OpenAlex
- W2374078013
- Cited by
- 294
- References
- 49
- FWCI
- 17.14
- Type
- journal article
- Language
- en
- Open access
- bronze
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