Menin mediates epigenetic regulation via histone H3 lysine 9 methylation

111

Neuroendocrine tumours (NET) of the gastrointestinal tract and the lung are a rare and heterogeneous group of tumours. The molecular characterization and the clinical classification of these tumours have been evolving slowly and show differences according to organs of origin. Novel technologies such as next-generation sequencing revealed new molecular aspects of NET over the last years. Notably, whole-exome/genome sequencing (WES/WGS) approaches underlined the very low mutation rate of well-differentiated NET of all organs compared to other malignancies, while the engagement of epigenetic changes in driving NET evolution is emerging. Indeed, mutations in genes encoding for proteins directly involved in chromatin remodelling, such as DAXX and ATRX are a frequent event in NET. Epigenetic changes are reversible and targetable; therefore, an attractive target for treatment. The discovery of the mechanisms underlying the epigenetic changes and the implication on gene and miRNA expression in the different subgroups of NET may represent a crucial change in the diagnosis of this disease, reveal new therapy targets and identify predictive markers. Molecular profiles derived from omics data including DNA mutation, methylation, gene and miRNA expression have already shown promising results in distinguishing clinically and molecularly different subtypes of NET. In this review, we recapitulate the major genetic and epigenetic characteristics of pancreatic, lung and small intestinal NET and the affected pathways. We also discuss potential epigenetic mechanisms leading to NET development.

Section: Men1 Men1 Is the Most Frequently Mutated Gene Inmentioning

confidence: 99%

Genetic and epigenetic drivers of neuroendocrine tumours (NET)

Domenico

Wiedmer

Perren

2017

111

“…Menin can be recruited to the promotor of the homeobox gene GBX2 through interaction with the histone lysine methyltransferase SUV39H1. This interaction induced H3K9 trimethylation at the gene promoter, providing the repressive chromatin environment for downregulation of GBX2 transcription (Yang et al 2013; Fig. 2C).…”

Section: Menin As An Epigenetic Repressor Of Gene Transcriptionmentioning

confidence: 99%

Thoracic and duodenopancreatic neuroendocrine tumors in multiple endocrine neoplasia type 1: natural history and function of menin in tumorigenesis

Pieterman¹,

Conemans²,

Dreijerink³

et al. 2014

Mutations of the multiple endocrine neoplasia type 1 (MEN1) gene lead to loss of function of its protein product menin. In keeping with its tumor suppressor function in endocrine tissues, the majority of the MEN1-related neuroendocrine tumors (NETs) show loss of heterozygosity (LOH) on chromosome 11q13. In sporadic NETs, MEN1 mutations and LOH are also reported, indicating common pathways in tumor development. Prevalence of thymic NETs (thNETs) and pulmonary carcinoids in MEN1 patients is 2-8%. Pulmonary carcinoids may be underreported and research on natural history is limited, but disease-related mortality is low. thNETs have a high mortality rate. Duodenopancreatic NETs (dpNETs) are multiple, almost universally found at pathology, and associated with precursor lesions. Gastrinomas are usually located in the duodenal submucosa while other dpNETs are predominantly pancreatic. dpNETs are an important determinant of MEN1-related survival, with an estimated 10-year survival of 75%. Survival differs between subtypes and apart from tumor size there are no known prognostic factors. Natural history of nonfunctioning pancreatic NETs needs to be redefined because of increased detection of small tumors. MEN1-related gastrinomas seem to behave similar to their sporadic counterparts, while insulinomas seem to be more aggressive. Investigations into the molecular functions of menin have led to new insights into MEN1-related tumorigenesis. Menin is involved in gene transcription, both as an activator and repressor. It is part of chromatin-modifying protein complexes, indicating involvement of epigenetic pathways in MEN1-related NET development. Future basic and translational research aimed at NETs in large unbiased cohorts will clarify the role of menin in NET tumorigenesis and might lead to new therapeutic options.

“…Menin has been reported to silence transcription of target genes via interacting with the suppressor of variegation 3–9homolog protein 1 (SUV39H1) and increasing the histone 3 lysine 9 trimethylation (H3K9me3) at the promoter of the target genes (Feng, et al 2017; Song, et al 2014; Yang, et al 2013). SUV39H1 is a histone 3 lysine 9 (H3K9) methyltransferase (Rea, et al 2000).…”

Section: Introductionmentioning

confidence: 99%

“…SUV39H1 is a histone 3 lysine 9 (H3K9) methyltransferase (Rea, et al 2000). Menin interacts with SUV39H1 through 360–445 amino acid region of menin and recruits SUV39H1 to the promoters of GBX2 and IL6 and represses their expression via enhancing H3K9me3 (Song et al 2014; Yang et al 2013). Recently, we found that menin directly binds to Daxx/ATRX complex and further recruits SUV39H1 to the promoter of membrane metallo-endopeptidase (Mme, or CD10), and represses Mme expression by enhancing H3K9me3 at the Mme promoter (Feng et al 2017).…”

Section: Introductionmentioning

confidence: 99%

“…Menin and Daxx are required for each other to recruit SUV39H1 to the Mme promoter, and menin directly binds to Daxx through 396–450 amino acid region (Feng et al 2017). Daxx also directly binds to ATRX which may also bind SUV39H1 binding domain (Feng et al 2017; Tang, et al 2004; Yang et al 2013). These findings suggest that menin and Daxx/ATRX firstly form a complex and then recruit SUV39H1 to the Mme promoter and increase H3K9me3, leading to suppression of Mme expression.…”

Section: Introductionmentioning

confidence: 99%

See 1 more Smart Citation

Epigenetic regulation by the menin pathway

Feng¹,

Ma²,

Hua³

2017

There is a trend of increasing prevalence of neuroendocrine tumors (NETs), and the inherited multiple endocrine neoplasia type 1 (MEN1) syndrome serves as a genetic model to investigate how NETs develop and the underlying mechanisms. Menin, encoded by the MEN1 gene, at least partly acts as a scaffold protein by interacting with multiple partners to regulate cellular homeostasis of various endocrine organs. Menin has multiple functions including regulating several important signaling pathways by controlling gene transcription. Here, we focus on reviewing the recent progress in elucidating the key biochemical role of menin in epigenetic regulation of gene transcription and cell signaling, as well as posttranslational regulation of menin itself. In particular, we will review the progress in studying structural and functional interactions of menin with various histone modifiers and transcription factors such as MLL, PRMT5, SUV39H1 and other transcription factors including c-Myb and JunD. Moreover, the role of menin in regulating cell signaling pathways such as TGF-beta, Wnt, and Hedgehog, as well as miRNA biogenesis and processing will be described. Further, the regulation of the MEN1 gene transcription, posttranslational modifications and stability of menin protein will be reviewed. These various modes of regulation by menin as well as regulation of menin by various biological factors broaden the view regarding how menin controls various biological processes in neuroendocrine organ homeostasis.