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 Kras G12D 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.

Fbxl10 overexpression in murine hematopoietic stem cells induces leukemia involving metabolic activation and upregulation of Nsg2

“…5 In addition, IMP2-positive glioma and PPARGC1A (PGC1a)-positive melanoma showed tumor progression associated with mitochondrial energy activation in the absence and presence of enhanced ROS levels, respectively. 39,40 Thus, despite the general enhancement of glycolytic bioenergetic requirements in many cancers (so called as "Warburg effect"), several recent studies have revealed unanticipated tumor metabolism by Warburg, that is, the bioenergetic type of tumors can vary widely from glycolysis to OXPHOS.…”

“…Taken together with the upregulation of FBXL10 in human leukemia and solid tumors, [3][4][5][6] selective inhibition of FBXLl10 may be a therapeutic strategy to achieve improvement in these diseases. Figure 7.…”

“…2 Clinically, an elevated expression of Fbxl10 is observed in patients with acute myeloid leukemia (AML) or acute lymphoid leukemia (ALL), seminoma, and pancreatic ductal adenocarcinoma. [3][4][5][6] These findings prompted us to further investigate the role of Fbxl10 in leukemia development in vivo.…”

“…6,11 In addition, wild-type (WT) Fbxl10 but not a demethylase activity-deficient mutant, accelerated the progression of pancreatic cancer in a mouse allograft model. 5 Fbxl10 is highly expressed in lineage marker (Lin) 2 , Sca-1 1 , c-Kit 1 (LSK) cells and Lin 2 undifferentiated bone marrow (BM) cells, and forced expression of Fbxl10 in hematopoietic stem cells (HSCs) retained high BM repopulation capacity. 12 Furthermore, another study demonstrated that the demethylase enzymatic activity was required for leukemic transformation in a Hoxa9-Meis1-induced mouse BM transplantation model.…”

“…2 Clinically, an elevated expression of Fbxl10 is observed in patients with acute myeloid leukemia (AML) or acute lymphoid leukemia (ALL), seminoma, and pancreatic ductal adenocarcinoma. [3][4][5][6] These findings prompted us to further investigate the role of Fbxl10 in leukemia development in vivo.Fbxl10 belongs to the JmjC domain-containing histone demethylases, and contains an N-terminal JmjC domain, followed by a CXXC zinc finger domain, a plant homeodomain finger, an F-box, and 8 leucine-rich repeats. 7 Fbxl10 preferentially demethylates the dimethylation of histone H3 at lysine 36 (H3K36me2), but not H3K36me1 and H3K36me3.…”