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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Research Article Oncology

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 1

KDM2B is upregulated in advanced PDAC.

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KDM2B is upregulated in advanced PDAC. (A) Heat map of quantitative RT-P...
(A) Heat map of quantitative RT-PCR data showing relative expression of HDM family members in human PDAC cell lines versus HPDE cells. Color bar indicates relative fold change. (B) KDM2B transcript levels in a series of human PDAC specimens compared with normal pancreatic tissue, determined by RNA-seq (samples from MGH tumor bank). (C–F) IHC staining for KDM2B in human pancreatic tissues. (C) Normal (N.) adult pancreas was negative for KDM2B. Insets: higher magnification of normal duct and islet. (D) PDAC showing strong nuclear expression in neoplastic cells, whereas normal duct cells were negative. Insets: higher magnification of PDAC cells (top) and normal duct (bottom). (E) Primary PDAC showing stronger staining of the poorly differentiated component (arrows) compared with the well-differentiated glandular component (asterisks). Insets: Higher magnification of poorly differentiated (top) and glandular (bottom) elements. (F) PDAC liver metastasis showed strong staining of tumor cells, whereas normal liver parenchyma was negative. Inset: higher magnification of PDAC cells (top) and normal liver (bottom). Scale bars: 50 μm; 20 μm (insets). (G) Relative KDM2B IHC staining score for 69 primary PDAC specimens of different grades. (H) Percent distribution of KDM2B staining scores in primary and metastatic tumors. (I) Quantitative RT-PCR analysis of relative KDM2B expression in PDAC cell lines versus HPDE and HPNE cells. Cell lines were classified as quasimesenchymal (QM) and classical based on ref. 4. See also Supplemental Figure 1.