title: KDM2B promotes pancreatic cancer via Polycomb-dependent and -independent transcriptional programs.
abstract: Epigenetic mechanisms mediate heritable control of cell identity in normal cells and cancer. We sought to identify epigenetic regulators driving the pathogenesis of pancreatic ductal adenocarcinoma (PDAC), one of the most lethal human cancers. We found that KDM2B (also known as Ndy1, FBXL10, and JHDM1B), an H3K36 histone demethylase implicated in bypass of cellular senescence and somatic cell reprogramming, is markedly overexpressed in human PDAC, with levels increasing with disease grade and stage, and highest expression in metastases. KDM2B silencing abrogated tumorigenicity of PDAC cell lines exhibiting loss of epithelial differentiation, whereas KDM2B overexpression cooperated with KrasG12D to promote PDAC formation in mouse models. Gain- and loss-of-function experiments coupled to genome-wide gene expression and ChIP studies revealed that KDM2B drives tumorigenicity through 2 different transcriptional mechanisms. KDM2B repressed developmental genes through cobinding with Polycomb group (PcG) proteins at transcriptional start sites, whereas it activated a module of metabolic genes, including mediators of protein synthesis and mitochondrial function, cobound by the MYC oncogene and the histone demethylase KDM5A. These results defined epigenetic programs through which KDM2B subverts cellular differentiation and drives the pathogenesis of an aggressive subset of PDAC.
authors: Massachusetts General Hospital Cancer Center, Boston, Massachusetts, USA. Tzatsos.Alexandros@mgh.harvard.edu
authors: Alexandros
authors: A
authors: Tzatsos
authors: Polina
authors: P
authors: Paskaleva
authors: Francesco
authors: F
authors: Ferrari
authors: Vikram
authors: V
authors: Deshpande
authors: Svetlana
authors: S
authors: Stoykova
authors: Gianmarco
authors: G
authors: Contino
authors: Kwok-Kin
authors: KK
authors: Wong
authors: Fei
authors: F
authors: Lan
authors: Patrick
authors: P
authors: Trojer
authors: Peter J
authors: PJ
authors: Park
authors: Nabeel
authors: N
authors: Bardeesy
mesh_terms: D000818:Animals; D021441:Carcinoma, Pancreatic Ductal / Q000209:etiology* / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D045744:Cell Line, Tumor; D004195:Disease Models, Animal; D044127:Epigenesis, Genetic; D044783:F-Box Proteins / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D056484:Jumonji Domain-Containing Histone Demethylases / Q000235:genetics / Q000378:metabolism*; D051379:Mice; D016513:Mice, SCID; D010089:Oxidoreductases, N-Demethylating / Q000235:genetics / Q000378:metabolism*; D010190:Pancreatic Neoplasms / Q000209:etiology* / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D063146:Polycomb-Group Proteins / Q000235:genetics / Q000378:metabolism*; D016283:Proto-Oncogene Proteins p21(ras) / Q000235:genetics / Q000378:metabolism; D014158:Transcription, Genetic; D015854:Up-Regulation
chemical_list: D044783:F-Box Proteins; D063146:Polycomb-Group Proteins; D056484:Jumonji Domain-Containing Histone Demethylases; C534524:KDM2A protein, human; C524747:Kdm2b protein, mouse; D010089:Oxidoreductases, N-Demethylating; C495971:Hras protein, mouse; D016283:Proto-Oncogene Proteins p21(ras)