Epigenetic regulation of somatostatin and somatostatin receptors in neuroendocrine tumors and other types of cancer
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Epigenetic regulation of somatostatin and somatostatin receptors in neuroendocrine tumors and other types of cancer M.J. Klomp 1,2 & S.U. Dalm 2 & M. de Jong 2 & R.A. Feelders 1 & J. Hofland 1 & L.J. Hofland 1 Accepted: 9 October 2020 # The Author(s) 2020
Abstract Both somatostatin (SST) and somatostatin receptors (SSTRs) are proteins with important functions in both physiological tissue and in tumors, particularly in neuroendocrine tumors (NETs). NETs are frequently characterized by high SSTRs expression levels. SST analogues (SSAs) that bind and activate SSTR have anti-proliferative and anti-secretory activity, thereby reducing both the growth as well as the hormonal symptoms of NETs. Moreover, the high expression levels of SSTR type-2 (SSTR2) in NETs is a powerful target for therapy with radiolabeled SSAs. Due to the important role of both SST and SSTRs, it is of great importance to elucidate the mechanisms involved in regulating their expression in NETs, as well as in other types of tumors. The field of epigenetics recently gained interest in NET research, highlighting the importance of this process in regulating the expression of gene and protein expression. In this review we will discuss the role of the epigenetic machinery in controlling the expression of both SSTRs and the neuropeptide SST. Particular attention will be given to the epigenetic regulation of these proteins in NETs, whereas the involvement of the epigenetic machinery in other types of cancer will be discussed as well. In addition, we will discuss the possibility to target enzymes involved in the epigenetic machinery to modify the expression of the SST-system, thereby possibly improving therapeutic options. Keywords Neuroendocrine tumors . Cancer . Somatostatin . Somatostatin receptor . Epigenetic regulation
1 Introduction Somatostatin receptors (SSTRs) are a family of G protein coupled receptors, of which different subtypes exist, i.e. SSTR1, SSTR2, SSTR3, SSTR4 and SSTR5. Alternative splicing of SSTR2 RNA generates two splice variants: SSTR2a and SSTR2b which differ in length. SSTRs can be activated by the neuropeptide somatostatin (SST), of which two isoforms are known, i.e. somatostatin-14 (SST-14) and somatostatin-28 (SST-28), both having high affinity for SSTRs [1, 2]. SST is produced by different organs in both the central nervous system, e.g. hypothalamus, and in other organs including pancreas, stomach and intestine. It is synthesized in response to multiple biological signals, for instance neurotransmitters, hormones and neuropeptides [3]. SSTR* L.J. Hofland [email protected] 1
Department of Internal Medicine, Division of Endocrinology, Erasmus MC, Rotterdam, The Netherlands
2
Department of Radiology & Nuclear Medicine, Erasmus MC, Rotterdam, The Netherlands
expressing cells are found abundantly in human tissues, such as the brain, pituitary and the gastrointestinal tract [4]. The SST-system is therefore involved in regulating multiple physiological processes. This is mediated via several pathways that are activated upon bi
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