Epigenetic regulation in the tumorigenesis of MEN1-associated endocrine cell types

Abstract

Epigenetic regulation is emerging as a key feature in the molecular characteristics of various human diseases. Epigenetic aberrations can occur from mutations in genes associated with epigenetic regulation, improper deposition, removal or reading of histone modifications, DNA methylation/demethylation and impaired non-coding RNA interactions in chromatin. Menin, the protein product of the gene causative for the multiple endocrine neoplasia type 1 (MEN1) syndrome, interacts with chromatin-associated protein complexes and also regulates some non-coding RNAs, thus participating in epigenetic control mechanisms. Germline inactivating mutations in the gene that encodes menin predispose patients to develop endocrine tumors of the parathyroids, anterior pituitary and the duodenopancreatic neuroendocrine tissues. Therefore, functional loss of menin in the various MEN1-associated endocrine cell types can result in epigenetic changes that promote tumorigenesis. Because epigenetic changes are reversible, they can be targeted to develop therapeutics for restoring the tumor epigenome to the normal state. Irrespective of whether epigenetic alterations are the cause or consequence of the tumorigenesis process, targeting the endocrine tumor-associated epigenome offers opportunities for exploring therapeutic options. This review presents epigenetic control mechanisms relevant to the interactions and targets of menin, and the contribution of epigenetics in the tumorigenesis of endocrine cell types from menin loss.

Clinicopathological features and menin expression of pancreatic neuroendocrine neoplasm associated with multiple endocrine neoplasia type 1

“…And menin is protein encoded by MEN1. 5 In pNEN development, menin has been reported to be both an activator and repressor of gene transcription and has been associated with several pathways of tumor development 6 . To date, there have been few reports that have analyzed M‐pNEN focusing on the expression of menin in pNEN.…”

“…5 In pNEN development, menin has been reported to be both an activator and repressor of gene transcription and has been associated with several pathways of tumor development. 6 To date, there have been few reports that have analyzed M-pNEN focusing on the expression of menin in pNEN. Investigations of clinicopathological differences in between M-pNEN and S-pNEN may help in determining treatment strategies.…”

Prognostic factors for the outcome of nonfunctioning pancreatic neuroendocrine tumors in MEN1: a systematic review of literature

“…In addition, they show that despite numerous efforts, no definitive genotype-phenotype correlation has been identified in MEN1-related pNETs mainly due to lack of validation of reported associations, and therefore, we currently do not recommend basing management decisions on a specific genotype (Thevenon et al 2013, Bartsch et al 2014, Giudici et al 2017, Christakis et al 2018. A biological reason for the lack of validated genotype-phenotype correlations may be that menin does not have intrinsic enzymatic activity and is involved in multiple cellular processes (most importantly epigenetic regulation of gene transcription) through interaction with other proteins (Iyer & Agarwal 2018). It might therefore also be of value to investigate if variants in genes coding for menininteracting proteins might modify the phenotype, such as been suggested in a publication showing that patients with CDKN1B V109G polymorphism had more aggressive tumors (Circelli et al 2015).…”

Familial Hyperparathyroidism

“…It is now recognized that thymic NETs, a rare but aggressive tumor, carry the highest odds ratio of death among MEN1 patients (63). Nevertheless, given the rarity of these thymic tumors, pancreatic NET are the main focus of therapeutic interventions to improve MEN1 mortality (64)(65)(66).…”