Epigenetic regulation of somatostatin and somatostatin receptors in neuroendocrine tumors and other types of cancer

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: Cancer; Epigenetic regulation; Neuroendocrine tumors; Somatostatin; Somatostatin receptor.

Fig. 1

(a) Upon binding of SST or SSAs, (1,2) K⁺ channels are activated and Ca²⁺ channels are inhibited, resulting in decreased Ca²⁺ levels, and (3) adenylyl cyclase (AC) activity is inhibited thereby reducing intracellular cAMP levels. This results in inhibition of hormone secretion. (b) Activation of the SST-system also results in anti-tumoral activity: (1) SHP-1 is activated, thereby increasing pro-apoptotic and reducing anti-apoptotic proteins, and (2) SHP-2 is activated which results in activation of PTPη by Src-mediated phosphorylation. PTPη causes inhibition of pathways physiologically involved in cell proliferation. In both figure a and b, effects induced by SSTR activation are indicated by green (enhanced) or red (reduced) arrows

Fig. 2

(a) Epigenetic modifications can modify both DNA and histones. DNA methylation and inactivating histone methylation stimulate heterochromatin, resulting in inaccessible DNA and therefore no gene transcription. Histone acetylation and activating histone methylation stimulate euchromatin, thereby stimulating gene transcription. Histone methylation can therefore both be inactivating and activating, depending on which lysine residue is modified on which histone. Examples of inactivating histone methylation marks (indicated in red) are H3K9me2/3, H3K27me2/3 and H4K20me3, and activating histone methylation marks (indicated in green) are H3K4me2/3, H2K36me3 and H3K79me3. All epigenetic modifications are catalyzed by enzymes: (1) DNA methylation by DNMTs, (2) histone methylation marks by HMTs and HDMs, and (3) histone acetylation marks by HATs and HDACs. (b) DNMTs are involved in DNA methylation in which cytosine residues are converted into 5-methylcytosine residues. (c,d) Epigenetic drugs have been developed inhibiting certain groups of enzymes involved in epigenetic modifications, i.e. DNMTis and HDACis targeting DNMTs and HDACs, respectively, both stimulating transcriptionally active euchromatin. (e) HDACis often target multiple HDACs within HDAC class I, IIa and/or IIb. AB3, entinostat (ENT), tacedinaline (TAC), thailandepsin-A (TDP-A) and valproic acid (VPA) target HDAC1, 2 and 3; romidepsin (FK228) targets all HDAC protein within class I; LMK235 targets HDAC4 and 5 within class IIa; vorinostat (SAHA) and trichostatin A (TSA) target HDAC proteins within class I, IIa and IIb. [, –106]

Fig. 3

Activating histone marks (indicated in green) stimulate euchromatin, resulting in more gene transcription. Epigenetic drugs may be used to stimulate euchromatin, in order to increase the expression of certain proteins. Thereby, it may be possible to increase the expression of targets for therapy, e.g. SSTR2 in NET patients with insufficient expression levels for treatment