KDM2B promotes pancreatic cancer via Polycomb-dependent and -independent transcriptional programs
Alexandros Tzatsos, … , Peter J. Park, Nabeel Bardeesy
Alexandros Tzatsos, … , Peter J. Park, Nabeel Bardeesy
Published January 16, 2013
Citation Information: J Clin Invest. 2013;123(2):727-739. https://doi.org/10.1172/JCI64535.
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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

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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Figure 6

Differential roles of KDM2B in chromatin regulation at activated and repressed targets.

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Differential roles of KDM2B in chromatin regulation at activated and rep...
(A) ChIP analysis of MiaPaca cells for binding of the indicated proteins to different KDM2B-EZH2 and KDM2B-KDM5A-MYC targets. (B and C) Quantitative RT-PCR analysis of expression changes of selected genes cobound by KDM2B-EZH2 or KDM2B-KDM5A-MYC in response to knockdown of (B) KDM2B or (C) EZH2, MYC, and KDM5A. Cobinding modules are represented by ovals. Note that genes cobound by KDM2B-EZH2 were upregulated upon KDM2B or EZH2 knockdown, whereas KDM2B-KDM5A-MYC–cobound genes were downregulated upon KDM2B, c-MYC, or KDM5A knockdown. (D) ChIP analysis showing the effect of KDM2B knockdown on the indicated histone marks and on binding of EZH2 and RING1B at selected KDM2B target genes in MiaPaca cells. Change in mRNA expression induced by KDM2B knockdown (RNA-seq) is also shown. Results are mean ± SD. *P < 0.05; **P < 0.01. (E) ChIP analysis showing relative fold enrichment of the indicated histone marks on selected target genes that define the different KDM2B modules in MiaPaca cells. KDM2B-EZH2–cobound and KDM2B-KDM5A–cobound genes are shown as blue and red bars, respectively. (F and G) The indicated PDAC cell lines were infected with shControl or shKDM2B lentiviruses and cultured for 36 hours in standard (25 mM) or reduced (1 mM) glucose concentrations. Attached and floating cells were analyzed (F) by Western blotting or (G) for viability (trypan blue dye exclusion method). See also Supplemental Figure 6 and Supplemental Table 3.