Document Detail


KDM2B promotes pancreatic cancer via Polycomb-dependent and -independent transcriptional programs.
MedLine Citation:
PMID:  23321669     Owner:  NLM     Status:  MEDLINE    
Abstract/OtherAbstract:
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:
Alexandros Tzatsos; Polina Paskaleva; Francesco Ferrari; Vikram Deshpande; Svetlana Stoykova; Gianmarco Contino; Kwok-Kin Wong; Fei Lan; Patrick Trojer; Peter J Park; Nabeel Bardeesy
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Publication Detail:
Type:  Journal Article; Research Support, N.I.H., Extramural; Research Support, Non-U.S. Gov't     Date:  2013-01-16
Journal Detail:
Title:  The Journal of clinical investigation     Volume:  123     ISSN:  1558-8238     ISO Abbreviation:  J. Clin. Invest.     Publication Date:  2013 Feb 
Date Detail:
Created Date:  2013-04-19     Completed Date:  2013-05-13     Revised Date:  2013-12-04    
Medline Journal Info:
Nlm Unique ID:  7802877     Medline TA:  J Clin Invest     Country:  United States    
Other Details:
Languages:  eng     Pagination:  727-39     Citation Subset:  AIM; IM    
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MeSH Terms
Descriptor/Qualifier:
Animals
Carcinoma, Pancreatic Ductal / etiology*,  genetics,  metabolism,  pathology
Cell Line, Tumor
Disease Models, Animal
Epigenesis, Genetic
F-Box Proteins / genetics,  metabolism*
Humans
Jumonji Domain-Containing Histone Demethylases / genetics,  metabolism*
Mice
Mice, SCID
Oxidoreductases, N-Demethylating / genetics,  metabolism*
Pancreatic Neoplasms / etiology*,  genetics,  metabolism,  pathology
Polycomb-Group Proteins / genetics,  metabolism*
Proto-Oncogene Proteins p21(ras) / genetics,  metabolism
Transcription, Genetic
Up-Regulation
Grant Support
ID/Acronym/Agency:
1 R01 CA133557-01/CA/NCI NIH HHS; K99 CA158582/CA/NCI NIH HHS; K99 CA158582/CA/NCI NIH HHS; P01 CA117969/CA/NCI NIH HHS; P01 CA117969-06/CA/NCI NIH HHS; P50 CA127003/CA/NCI NIH HHS; R01 CA133557/CA/NCI NIH HHS
Chemical
Reg. No./Substance:
0/F-Box Proteins; 0/Polycomb-Group Proteins; EC 1.14.11.-/Jumonji Domain-Containing Histone Demethylases; EC 1.14.11.27/KDM2A protein, human; EC 1.14.11.27/Kdm2b protein, mouse; EC 1.5.-/Oxidoreductases, N-Demethylating; EC 3.6.5.2/Kras2 protein, mouse; EC 3.6.5.2/Proto-Oncogene Proteins p21(ras)
Comments/Corrections

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