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KDM2B promotes pancreatic cancer via Polycomb-dependent and -independent transcriptional programs.

Authors: Tzatsos, A  Paskaleva, P  Ferrari, F  Deshpande, V  Stoykova, S  Contino, G  Wong, KK  Lan, F  Trojer, P  Park, PJ  Bardeesy, N 
Citation: Tzatsos A, etal., J Clin Invest. 2013 Feb 1;123(2):727-39. doi: 10.1172/JCI64535. Epub 2013 Jan 16.
Pubmed: (View Article at PubMed) PMID:23321669
DOI: Full-text: DOI:10.1172/JCI64535

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.

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CRRD Object Information
CRRD ID: 9588253
Created: 2014-10-23
Species: All species
Last Modified: 2014-10-23
Status: ACTIVE



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RGD is funded by grant HL64541 from the National Heart, Lung, and Blood Institute on behalf of the NIH.