Table 1.

Epigenetic mechanisms involved in MEN1-related pNET tumorigenesis.

Epigenetic Mechanism	Consequence of Loss of Menin Function	Effect	Role in MEN1 pNET Tumorigenesis
Histone 3 methylation	Loss of H3K4me3 and increase of H3K27me3	Downregulation of target gene expression mainly linked to beta cell endocrine function (IGF2BP2)	Development of functioning tumors of the beta cells of the pancreas
Histone 3 methylation	Loss of H3K9me3	Overexpression of MME gene	Increased and uncontrolled growth of neuroendocrine cells. Risk of liver metastases
Histone 4 methylation	Loss of the PRMT5-mediated H4R3me2	Expression of GAS1 gene and subsequent activation of the Hedgehog signaling	Upregulation of tumor cell growth at beta islets
DNA methylation	Hypermethylation of CpG at CASP8 gene promoter	Repression of CASP8 gene expression	Prevention of apoptosis of tumor cells
DNA methylation	Hypermethylation of CpG at RASSF1 gene promoter	Repression of RASSF1 tumor suppressor gene expression	Loss of cell cycle arrest and promotion of cell growth
DNA methylation	Hypermethylation of CpG at MGMT gene promoter	Repression of MGMT gene expression	Loss of the protective action of the O-6-methylguanine-DNA- methyltransferase against exogenous alkylating agents, which are potent carcinogens

IGF2BP2 = Insulin-like Growth Factor 2 mRNA Binding Protein 2; MME = Membrane Metallo-Endopeptidase; PRMT5 = Protein Arginine Methyltransferase 5; GAS1 = Growth Arrest Specific 1; CASP8 = caspase 8; RASSF1 = Ras Association Domain Family Member 1; MGMT = O-6-Methylguanine-DNA Methyltransferase.