KDM2B

Official Full Name

lysine demethylase 2B

Organism

Homo sapiens

GeneID

84678

Background

This gene encodes a member of the F-box protein family which is characterized by an approximately 40 amino acid motif, the F-box. The F-box proteins constitute one of the four subunits of ubiquitin protein ligase complex called SCFs (SKP1-cullin-F-box), which function in phosphorylation-dependent ubiquitination. The F-box proteins are divided into 3 classes: Fbws containing WD-40 domains, Fbls containing leucine-rich repeats, and Fbxs containing either different protein-protein interaction modules or no recognizable motifs. The protein encoded by this gene belongs to the Fbls class. Multiple alternatively spliced transcript variants have been found for this gene, but the full-length nature of some variants has not been determined. [provided by RefSeq, Jul 2008]

Synonyms

CXXC2; Fbl10; PCCX2; FBXL10; JHDM1B;

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Detailed Information

Recent Research

KDM2B (also known as FBXL10 or JHDM1B), originally known as dimethylated demethylase at lysine 4 and 36 for histone H3 (H3K36me2), is a non-classical polycomb inhibitor complex 1 Member of (PRC1). This complex also regulates gene expression by interacting with the loop e3 ubiquitin ligase. KDM2B is a cell growth regulator. KDM2B regulates adipocyte differentiation and prevents mouse embryonic stem cell differentiation. KDM2B plays a role at the beginning of the reprogramming process and enhances the activation of early response genes during the reprogramming process. It promotes gene activation by binding to gene promoters and demethylated gene promoters. KDM2B is up-regulated by inhibition of the Ink4a/Arf locus and other tumor suppressor pathways and exhibits primitive production activity. KDM2B plays an important role in hematological malignancies, gynecology (breast cancer, cervical cancer, and ovarian cancer), pancreatic cancer, gastric cancer, and self-renewal of cancer stem cells. Data from the murine model indicates that inhibition of KDM2B in leukemia stem cells impedes the development of significant leukemia.

KDM2B inhibits Ink4/Arf (a family of kinase inhibitors dependent on cycline) by EZH2 (an enhancer of zeste homolog 2), a catalytic subunit of polycomb inhibitor complex 2, a highly conserved histone methyl group. The transferase, targeting lysine-27 of histone H3, interferes with cell proliferation and cellular senescence. KDM2B promotes transcriptional repression through let-7b and EZH2. Silencing of KDM2B resulted in elevated levels of let-7b. In addition, the up-regulation of let-7b is accompanied by a downward adjustment of EZH2. Since overexpression of KDM2B promotes cell proliferation (increased s phase entry and G2-M transition), downregulation of let-7b is expected to interfere with cell proliferation.

KDM2B functions as a GC (gastric carcinom) suppressor by inhibiting Myc-mediated glycolysis. KDM2B as the target of miR-448 represses glycolysis and promotes oxidative phosphorylation. Overexpression of miR-448 reduced both the mRNA and protein levels of KDM2B, whereas KDM2B re-expression abrogated the miR-448-mediated glycolytic activities. Furthermore, Myc as a key target of KDM2B that controls metabolic switch in GC. In addition, enhanced miR-448 level was significantly associated with poor clinical outcomes of GC patients.

KDM2B also has the ability to promote the production of pluripotent stem cells (iPSCs). This ability depends on its demethylase and DNA binding activity, but is largely independent of its ability to antagonize aging. KDM2B functions at the beginning of the reprogramming process and enhances the activation of early response genes in reprogramming. KDM2B promotes gene activation by binding to and demethylation of gene promoters. Loss of short-term KDM2B can alter the epigenetic landscape of tumor cells, favoring apoptosis, and the long-term consequences of the epigenome can reduce proliferation without the need for additional external apoptotic stimuli. KDM2B can alter the apoptotic response of GBM cells to TRAIL-induced apoptosis and regulate the apoptotic response of pancreatic cancer cells.

On the other hand, KDM2B is required for the appropriate regulation of CKα (choline kinaseα）during neuronal differentiation and to the maintaining of the undifferentiated stage of neuroblast cells.KDM2B regulates CKα expression and, as a consequence, neuronal differentiation. During proliferation, KDM2B binds to the Box2 located in the Chka promoter repressing its transcription.

References:

Liang G,et al.Kdm2b promotes induced pluripotent stem cell generation by facilitating gene activation early in reprogramming. Nature Cell Biology, 2016, 14(5):457-66.
Hong X, et al. MiR-448 promotes glycolytic metabolism of gastric cancer by downregulating KDM2B. Oncotarget, 2016, 7(16):22092-22102.
Kottakis F, et al. NDY1/KDM2B functions as a master regulator of polycomb complexes and controls self-renewal of breast cancer stem cells. Cancer Research, 2014, 74(14):3935-3946.

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