Global expression profiling of murine MEN1‐associated tumors reveals a regulatory role for menin in transcription, cell cycle and chromatin remodelling

Abstract

Although the identification of menin-interacting partners and other evidence support a role for menin, the multiple endocrine neoplasia type 1 gene (MEN1) product, in regulating gene expression, little is known about the cellular pathways dysregulated by menin loss during tumorigenesis. The mouse models of MEN1 accurately mimic the human syndrome and provide an opportunity to assess the transcriptional effects of Men1 deletion in different endocrine tumor types to identify common pathway aberrations underlying tumorigenesis in MEN1-affected tissues. We compared the global gene expression profiles of pituitary adenomas and pancreatic islet tumors with control tissues from wild-type littermates. Amongst the 551 differentially expressed genes was significant over-representation of genes associated with chromatin remodelling, transcription and cell cycling, including some genes known to encode menin-binding partners, e.g., Rhox5 and Mll1. Consistent with increased cell-cycle transition from G1 to S phase was an elevation of Cdc7 expression in the tumors, which was confirmed by qRT-PCR using independent samples. In support of previous findings in islet tumors, we found down-regulation of the cell-cycle regulator, p18, in both the pancreatic islet and pituitary adenomas, suggesting that reduced p18 levels may be important for Men1-related tumorigenesis in multiple tissues. Surprisingly, we identified increased p16 transcript in pancreatic islet and pituitary tumors. This was accompanied by increased cytoplasmic localization p16 protein in tumor cells. The specific genes and general pathways we have found to be commonly dysregulated in MEN1 tumors, provide a platform for determining their roles in endocrine tumorigenesis. ' 2007 Wiley-Liss, Inc.

Reexpression of oncoprotein MafB in proliferative β-cells and Men1 insulinomas in mouse

“…Our work strongly suggests that MafB reexpression could be a key factor for b-cell proliferation, both in the context of physiopathological metabolic needs and that of tumorigenesis. Although previous reports have identified several genes with altered expression in mouse Men1 insulinoma (Fontaniere et al, 2006;Mould et al, 2007), the current study describes for the first time the altered expression of a transcription factor known to have a critical role during normal islet development in early Men1 b-cell neoplastic lesions. Considering the known oncogenic function of MafB in other tissues (Eyche`ne et al, 2008) and the effects of its overexpression on growth behavior of bTC3-cells observed in this study, we believe that MafB reexpression may fulfill a tissuespecific molecular link between menin inactivation and b-cell proliferation by increasing the expression of the cell cycle regulators.…”

Somatostatin stimulates menin gene expression by inhibiting protein kinase A

“…Recent studies suggest that menin exerts its transcriptional control through a global effect on chromatin structure (40). Expression arrays of menin-null mouse embryo fibroblasts have implicated a role for extracellular matrix proteins (27) but still do not provide insights into the predilection for neuroendocrine cells.…”

“…Menin also interacts with a number of transcription factors such as JunD and NF-B proteins (2,17,22). Additionally, menin associates with chromatin and the nuclear matrix to recruit histone deacetylase complexes (HDACs) through association with mSin3A, a general transcriptional corepressor (30,40). Yet, despite its impact on the cell cycle and potential link to endocrine neoplasias, no studies to date describe the mechanisms by which menin expression is regulated in the neuroendocrine cells of the gut, especially those that are the precursors for gastrinomas.…”

Genetic and epigenetic drivers of neuroendocrine tumours (NET)

“…Menin recruits the H3K4me3 histone methyltransferase mixed lineage leukaemia (MLL1) complex, which is crucial for regulating gene expression and chromatin remodelling (Agarwal et al 1999). Studies on mice with heterozygous loss of Men1 report upregulation of genes involved in histone methylation (MLL1) and histone acetylation (CHD4) or chromatin modification (SMARCC2, HIST4H4, SUV420H2, CBX6, HLFX, HDAC9, HDAC10) (Mould et al 2007, Lejonklou et al 2012. A decrease in global methylation level of histone H3K9me3 and H3K4me3 is observed in Men1(−/−) murine cells (Agarwal & Jothi 2012, Yang et al 2013.…”