Endocrine Abstracts

Epigenetic mechanisms are gaining increasing interest in oncology, both as drivers of tumourigenesis and as potential novel therapeutic targets. This is particularly relevant in neuroendocrine neoplasms (NENs), as a key tumour suppressor gene involved in NEN development, multiple endocrine neoplasia type 1 (MEN1), plays a critical role in epigenetic regulation of gene expression through micro RNA (miRNA) and histone modification pathways. MEN1 mutations can give rise to sporadic NENs, or those occurring as part of the MEN1 syndrome in which patients predominately develop parathyroid adenomas, and NENs of the pancreas, and pituitary. Investigation of these tumours in MEN1 models has revealed insights in to the utility of epigenetics in NENs for modulating cell proliferation. For example, menin (encoded by MEN1) knockout results in reduced expression of the miRNA’s miR-15a and miR-16-1 with a concomitant increase in the cell cycle regulator cyclin D1 expression, which promotes cell proliferation. In addition, menin is an essential component of histone methyltransferase and deacetylation complexes, interacting with proteins including mixed lineage leukaemia 1 (MLL1), MLL2 and protein arginine methyltransferase 5 (PRMT5). Current medical treatments for NENs have limited efficacy, therefore epigenetic inhibitors targeting these specific histone modification complexes offer a promising new class of drugs for NENs. Thus, JQ1, an inhibitor of the bromo and extra-terminal (BET) protein family that bind acetylated histones, can reduce proliferation and increase apoptosis of both pancreatic NEN cell lines and pancreatic NENs occurring in a conditional MEN1 knockout mouse model. Furthermore, JQ1 can decrease proliferation and increase apoptosis of the pituitary tumour cell line AtT20, as well as downregulate expression of the Pomc gene, and subsequently reduce adrenocorticotropic hormone (ACTH) secretion. Therefore, advancing our knowledge of epigenetic mechanisms may provide a novel therapeutic approach for the control of NEN growth, and hormone secretion.