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Regulation of cyclin B2 expression and cell cycle G2/m transition by menin.
Multiple endocrine neoplasia type 1 (MEN1) results from mutations in tumor suppressor gene Men1, which encodes nuclear protein menin. Menin up-regulates certain cyclin-dependent kinase inhibitors through increasing histone H3 lysine 4 (H3K4) methylation and inhibits G(0)/G(1) to S phase transition. However, little is known as to whether menin controls G(2)/M-phase transition, another important cell cycle checkpoint. Here, we show that menin expression delays G(2)/M phase transition and reduces expression of Ccnb2 (encoding cyclin B2). Menin associates with the promoter of Ccnb2 and reduces histone H3 acetylation, a positive chromatin marker for gene transcription, at the Ccnb2 locus. Moreover, Men1 ablation leads to an increase in cyclin B2 expression, histone H3 acetylation at the Ccnb2 locus, and G(2)/M transition. In contrast, knockdown of cyclin B2 diminishes the number of cells at M phase and reduces cell proliferation. Furthermore, menin interferes with binding of certain positive transcriptional regulators, such as nuclear factor Y (NF-Y), E2 factors (E2Fs), and histone acetyltransferase CREB (cAMP-response element-binding protein)-binding protein (CBP) to the Ccnb2 locus. Notably, MEN1 disease-related mutations, A242V and L22R, abrogate the ability of menin to repress cyclin B2 expression and G(2)/M transition. Both of the mutants fail to reduce the acetylated level of the Ccnb2 locus. Together, these results suggest that menin-mediated repression of cyclin B2 is crucial for inhibiting G(2)/M transition and cell proliferation through a previously unrecognized molecular mechanism for menin-induced suppression of MEN1 tumorigenesis.
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Epstein-Barr virus nuclear antigens 3C and 3A maintain lymphoblastoid cell growth by repressing p16INK4A and p14ARF expression.
Epstein-Barr virus (EBV) nuclear antigen 3C (EBNA3C) and EBNA3A are each essential for EBV conversion of primary human B lymphocytes into continuously proliferating lymphoblast cell lines (LCLs) and for maintaining LCL growth. We now find that EBNA3C and EBNA3A's essential roles are to repress p16(INK4A) and p14(ARF). In the absence of EBNA3C or EBNA3A, p16(INK4A) and p14(ARF) expression increased and cell growth ceased. EBNA3C inactivation did not alter p16(INK4A) promoter CpG methylation, but reduced already low H3K27me3, relative to resting B cells, and increased H3K4me3 and H3-acetylation, linking EBNA3C inactivation to histone modifications associated with increased transcription. Importantly, knockdown of p16(INK4A) or p14(ARF) partially rescued LCLs from EBNA3C or EBNA3A inactivation-induced growth arrest and knockdown of both rescued LCL growth, confirming central roles for p16(INK4A) and p14(ARF) in LCL growth arrest following EBNA3C or EBNA3A inactivation. Moreover, blockade of p16(INK4A) and p14(ARF) effects on pRb and p53 by human papilloma virus type 16 E7 and E6 expression, sustained LCL growth after EBNA3C or EBNA3A inactivation. These data indicate that EBNA3C and EBNA3A joint repression of CDKN2A p16(INK4A) and p14(ARF) is essential for LCL growth.
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IDH mutation impairs histone demethylation and results in a block to cell differentiation.
Recurrent mutations in isocitrate dehydrogenase 1 (IDH1) and IDH2 have been identified in gliomas, acute myeloid leukaemias (AML) and chondrosarcomas, and share a novel enzymatic property of producing 2-hydroxyglutarate (2HG) from α-ketoglutarate. Here we report that 2HG-producing IDH mutants can prevent the histone demethylation that is required for lineage-specific progenitor cells to differentiate into terminally differentiated cells. In tumour samples from glioma patients, IDH mutations were associated with a distinct gene expression profile enriched for genes expressed in neural progenitor cells, and this was associated with increased histone methylation. To test whether the ability of IDH mutants to promote histone methylation contributes to a block in cell differentiation in non-transformed cells, we tested the effect of neomorphic IDH mutants on adipocyte differentiation in vitro. Introduction of either mutant IDH or cell-permeable 2HG was associated with repression of the inducible expression of lineage-specific differentiation genes and a block to differentiation. This correlated with a significant increase in repressive histone methylation marks without observable changes in promoter DNA methylation. Gliomas were found to have elevated levels of similar histone repressive marks. Stable transfection of a 2HG-producing mutant IDH into immortalized astrocytes resulted in progressive accumulation of histone methylation. Of the marks examined, increased H3K9 methylation reproducibly preceded a rise in DNA methylation as cells were passaged in culture. Furthermore, we found that the 2HG-inhibitable H3K9 demethylase KDM4C was induced during adipocyte differentiation, and that RNA-interference suppression of KDM4C was sufficient to block differentiation. Together these data demonstrate that 2HG can inhibit histone demethylation and that inhibition of histone demethylation can be sufficient to block the differentiation of non-transformed cells.
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