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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 Article has an altmetric score of 18

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

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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 2

KDM2B is required for tumorigenicity of poorly differentiated PDAC cell lines.

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KDM2B is required for tumorigenicity of poorly differentiated PDAC cell ...
(A and B) Human PDAC cell lines (MiaPaca and PANC1) were infected with lentiviruses expressing empty vector (shControl) or 2 different shRNAs against KDM2B (shKDM2B) and assessed by (A) in vitro growth assays and (B) subcutaneous tumorigenesis (xenograft) experiments (see Methods). (C) Growth curve showing that overexpression of a nontargeted wild-type KDM2B construct (rKDM2B) rescued the proliferative arrest induced by shKDM2B. (D) Percent growth inhibition of a panel of PDAC cell lines upon knockdown of KDM2B (9 days after seeding). Results are mean ± SD. (E–G) Transplantable murine PanIN-PDAC progression model using Ptf1α-Cre;LSL-KrasG12D pancreatic ductal cells. Cells were transduced with lentiviruses to overexpress wild-type and JmjC domain deletion mutant (ΔJmjC) of KDM2B. EV, empty vector. (E) Schematic of model system. (F) Western blot of KDM2B expression in transduced ductal cells and in vitro growth curves. Asterisk denotes nonspecific (N.S.) band. (G) Histological images of the pancreas 4 weeks after orthotopic injection with 2 × 104 cells. Control KrasG12D cells failed to form tumors, whereas wild-type KDM2B induced poorly differentiated PDAC. Insets show high-magnification views of the boxed regions (enlarged ×4). Scale bars: 200 μm. See also Supplemental Figure 2.

Copyright © 2025 American Society for Clinical Investigation
ISSN: 0021-9738 (print), 1558-8238 (online)

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