Multiple endocrine neoplasia type 1 (MEN1) is a dominantly inherited
tumor syndrome characterized by development of various combinations of
tumors in multiple endocrine glands, including the pituitary, parathyroid or pancreas. MEN1 results from mutations in tumor suppressor gene Men1, which encodes
nuclear protein menin. Menin has been shown to preferentially repress cell proliferation in endocrine tissues including pancreatic beta cells. Herein, the present study was to explore the potential mechanisms underlying menin in repressing cell proliferation in mice MEN1
insulinoma. In the Gene Set Enrichment Analysis (GSEA), Ccnb2 (encoding
cyclin B2) was up-regulated in pancreatic islets of Men1-excised mice after 14-day
tamoxifen-feeding. Immunofluorescence with antibody against
cyclin B2 revealed that the expression of
cyclin B2 was greatly increased in MEN1
insulinoma. In Men1(-/-) cells, Men1 ablation leaded to an increase in
cyclin B2 expression. Immunofluorescent staining by phospho-H3S10 antibody revealed the increasing number of Men1(-/-) cells in mitosis. Cells were seeded at a density of 5 × 10(4), then counted on day 2, 4 and 6, and the cell growth curve revealed Men1 ablation increased the cell proliferation. In contrast, knockdown of
cyclin B2 by
shRNA diminished the number of cells in mitosis and reduced cell proliferation. Further,
chromatin immunoprecipitation (ChIP) assay indicated that menin affected the
histone modification of the promoter of Ccnb2 by reducing the level of
histone H3 lysine 4 tri-methylation (
H3K4me3) and
histone H3 acetylation but not affecting the level of
histone H3 lysine 9 tri-methylation (H3K9me3) or
histone H3 lysine 27 tri-methylation (H3K27me3). Our results suggest that menin may inhibit MEN1
insulinoma by suppressing
cyclin B2 expression via
histone modification.