SIRT6 Suppresses Pancreatic Cancer through Control of Lin28b

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

doi:10.1016/j.cell.2016.04.033

SIRT6 Suppresses Pancreatic Cancer through Control of Lin28b

Cell. 2016 Jun 2;165(6):1401-1415. doi: 10.1016/j.cell.2016.04.033. Epub 2016 May 12.

Authors

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

Affiliations

¹ The Massachusetts General Hospital Cancer Center, Harvard Medical School, Boston, MA 02114, USA; The MGH Center for Regenerative Medicine, Harvard Medical School, Boston, MA 02114, USA.
² The MGH Center for Regenerative Medicine, Harvard Medical School, Boston, MA 02114, USA.
³ Broad Technology Labs (BTL), The Broad Institute of Harvard and MIT, Cambridge, MA 02142, USA.
⁴ The Massachusetts General Hospital Cancer Center, Harvard Medical School, Boston, MA 02114, USA.
⁵ Department of Molecular Biology, The Massachusetts General Hospital, Boston, MA 02114, USA; Department of Pathology, Massachusetts General Hospital, Harvard Medical School, Boston, MA 02114, USA.
⁶ The Massachusetts General Hospital Cancer Center, Harvard Medical School, Boston, MA 02114, USA; The MGH Center for Regenerative Medicine, Harvard Medical School, Boston, MA 02114, USA; The Broad Institute of Harvard and MIT, Cambridge, MA 02142, USA. Electronic address: rmostoslavsky@mgh.harvard.edu.

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.

Publication types

Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't

MeSH terms

Acetylation
Adenocarcinoma / genetics*
Animals
Cell Line, Tumor
Chromatin Assembly and Disassembly
Epigenesis, Genetic
Female
Gene Expression Regulation, Neoplastic*
Genes, ras
Histones / metabolism
Humans
Male
Mice
Mice, Knockout
Pancreatic Neoplasms / genetics*
RNA-Binding Proteins / genetics*
RNA-Binding Proteins / metabolism
Sirtuins / genetics*
Tumor Suppressor Proteins / metabolism

Substances

Histones
LIN28B protein, human
RNA-Binding Proteins
Tumor Suppressor Proteins
SIRT6 protein, human
Sirtuins

Abstract

Publication types

MeSH terms

Substances

Grants and funding