title: SIRT6 Suppresses Pancreatic Cancer through Control of Lin28b.
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.
authors.affiliation: 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.
authors.forename: Sita
authors.initials: S
authors.lastname: Kugel
authors.affiliation: 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.
authors.forename: Carlos
authors.initials: C
authors.lastname: Sebastián
authors.affiliation: 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.
authors.forename: Julien
authors.initials: J
authors.lastname: Fitamant
authors.affiliation: 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.
authors.forename: Kenneth N
authors.initials: KN
authors.lastname: Ross
authors.affiliation: 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.
authors.forename: Supriya K
authors.initials: SK
authors.lastname: Saha
authors.affiliation: The MGH Center for Regenerative Medicine, Harvard Medical School, Boston, MA 02114, USA.
authors.forename: Esha
authors.initials: E
authors.lastname: Jain
authors.affiliation: Broad Technology Labs (BTL), The Broad Institute of Harvard and MIT, Cambridge, MA 02142, USA.
authors.forename: Adrianne
authors.initials: A
authors.lastname: Gladden
authors.affiliation: The Massachusetts General Hospital Cancer Center, Harvard Medical School, Boston, MA 02114, USA.
authors.forename: Kshitij S
authors.initials: KS
authors.lastname: Arora
authors.affiliation: The Massachusetts General Hospital Cancer Center, Harvard Medical School, Boston, MA 02114, USA.
authors.forename: Yasutaka
authors.initials: Y
authors.lastname: Kato
authors.affiliation: The Massachusetts General Hospital Cancer Center, Harvard Medical School, Boston, MA 02114, USA.
authors.forename: Miguel N
authors.initials: MN
authors.lastname: Rivera
authors.affiliation: 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.
authors.forename: Sridhar
authors.initials: S
authors.lastname: Ramaswamy
authors.affiliation: 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.
authors.forename: Ruslan I
authors.initials: RI
authors.lastname: Sadreyev
authors.affiliation: Broad Technology Labs (BTL), The Broad Institute of Harvard and MIT, Cambridge, MA 02142, USA.
authors.forename: Alon
authors.initials: A
authors.lastname: Goren
authors.affiliation: The Massachusetts General Hospital Cancer Center, Harvard Medical School, Boston, MA 02114, USA.
authors.forename: Vikram
authors.initials: V
authors.lastname: Deshpande
authors.affiliation: 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.
authors.forename: Nabeel
authors.initials: N
authors.lastname: Bardeesy
authors.affiliation: 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.
authors.forename: Raul
authors.initials: R
authors.lastname: Mostoslavsky
mesh_terms: D000107:Acetylation; D000230:Adenocarcinoma / Q000235:genetics*; D000818:Animals; D045744:Cell Line, Tumor; D042002:Chromatin Assembly and Disassembly; D044127:Epigenesis, Genetic; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D011905:Genes, ras; D006657:Histones / Q000378:metabolism; D006801:Humans; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D010190:Pancreatic Neoplasms / Q000235:genetics*; D016601:RNA-Binding Proteins / Q000235:genetics* / Q000378:metabolism; D037761:Sirtuins / Q000235:genetics*; D025521:Tumor Suppressor Proteins / Q000378:metabolism
chemical_list: D006657:Histones; C516326:LIN28B protein, human; D016601:RNA-Binding Proteins; D025521:Tumor Suppressor Proteins; C516592:SIRT6 protein, human; D037761:Sirtuins