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.
Highlights
Somatostatin receptors (SSTRs) are a family of G protein coupled receptors, of which different subtypes exist, i.e. SSTR1, SSTR type-2 (SSTR2), SSTR3, SSTR4 and SSTR5
Understanding of the epigenetic mechanisms involved in the regulation of the expression of the SSTsystem is important for both neuroendocrine tumors (NETs) and other tumor types
Studies clearly prove the involvement of epigenetics in the regulation of SSTRs and SST expression in vitro, more indepth studies are required to confirm the ability to upregulate SSTR2 by using epigenetic drugs in vivo
Summary
Somatostatin receptors (SSTRs) are a family of G protein coupled receptors, of which different subtypes exist, i.e. SSTR1, SSTR2, SSTR3, SSTR4 and SSTR5. Upon binding of SST to SSTR, srchomology phosphatase (SHP) proteins are activated which are involved in regulating cell proliferation and apoptosis. SHP type-1 (SHP-1) is involved in inducing apoptosis by increasing pro-apoptotic proteins such as the p53-Baxcaspase-3 pathway and by increasing JNK expression resulting in inhibition of anti-apoptotic proteins (Fig. 1b). We will focus on the regulation of both proteins in different types of tumors, with particular emphasis on NETs. we will discuss the possibility to target the epigenetic machinery in order to modulate either SSTR or SST expression. An improved understanding of the epigenetic regulation involved in the SSTsystem may result in new approaches to either improve the efficacy of current treatments or expand therapeutic options for patients with tumors expression low SSTR levels
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