Epigenetic and post‐transcriptional regulation of somatostatin receptor subtype 5 (SST₅) in pituitary and pancreatic neuroendocrine tumors

Abstract

Somatostatin receptor subtype 5 (SST5) is an emerging biomarker and actionable target in pituitary (PitNETs) and pancreatic (PanNETs) neuroendocrine tumors. Transcriptional and epigenetic regulation of SSTR5 gene expression and mRNA biogenesis is poorly understood. Recently, an overlapping natural antisense transcript, SSTR5‐AS1, potentially regulating SSTR5 expression, was identified. We aimed to elucidate whether epigenetic processes contribute to the regulation of SSTR5 expression in PitNETs (somatotropinomas) and PanNETs. We analyzed the SSTR5/SSTR5‐AS1 human locus in silico to identify CpG islands. SSTR5 and SSTR5‐AS1 expression was assessed by quantitative real‐time PCR (qPCR) in 27 somatotropinomas, 11 normal pituitaries (NPs), and 15 PanNETs/paired adjacent (control) samples. We evaluated methylation grade in four CpG islands in the SSTR5/SSTR5‐AS1 genes. Results revealed that SSTR5 and SSTR5‐AS1 were directly correlated in NP, somatotropinoma, and PanNET samples. Interestingly, selected CpG islands were differentially methylated in somatotropinomas compared with NPs. In PanNETs cell lines, SSTR5‐AS1 silencing downregulated SSTR5 expression, altered aggressiveness features, and influenced pasireotide response. These results provide evidence that SSTR5 expression in PitNETs and PanNETs can be epigenetically regulated by the SSTR5‐AS1 antisense transcript and, indirectly, by DNA methylation, which may thereby impact tumor behavior and treatment response.

The uprise of RNA biology in neuroendocrine neoplasms: altered splicing and RNA species unveil translational opportunities

“…A natural antisense of somatostatin receptor subtype 5, SSTR5-AS1 has recently been reported to be upregulated in PanNEN tissue (as compared to non-tumoral adjacent tissue) where its levels were directly and strongly associated with SSTR5 expression in both tumor and non-tumor tissue. Moreover, in vitro assays revealed that SSTR5-AS1 influences both SSTR5 and its own expression, while its silencing enhances NEN cell aggressiveness features, including proliferation, migration, and colony formation, and, most importantly, influences the modest response of PanNEN cells to the SST 5 -preferring somatostatin analog pasireotide [ 101 ]. LncRNA KCNQ1OT1 was highly expressed in SCLC chemoresistant cells and its knockdown inhibited cell malignancy parameters in vitro through the activation of JAK2/STAT3 pathway [ 119 ].…”

The Role of Receptor–Ligand Interaction in Somatostatin Signaling Pathways: Implications for Neuroendocrine Tumors

“…The SSTR5 receptor is expressed in various tissues, including the nervous system, pancreas, basal ganglia, gastrointestinal tract, thyroid, and adrenal glands [ 1 , 24 , 37 ]. In the brain, the SSTR5 receptor is present in the hippocampus, cerebral cortex, hypothalamus, thalamus, lateral accumbens, and amygdala [ 38 , 39 ].…”

“…In addition, changes in chromatin structure and DNA methylation may affect the expression of SSTR genes. For example, methylation of the SSTR1, SSTR2, and SSTR5 gene promoters may influence their expression in cancer cells [ 14 , 37 ]. The use of histone deacetylase inhibitors may also affect the expression of SSTR receptors [ 71 ].…”

The role of DNA methylation in human pancreatic neuroendocrine tumours

“…Somatostatin analogues (SSAs) are the most commonly used medical therapy for patients with PNETs, with different SSA compounds having different affinities for the somatostatin receptor subtypes (SSTR 1–5 ). It has been reported that response to SSA treatment does not solely depend on the tumour receptor subtype expression and that other tumour factors modulate its treatment effect, for example, the natural antisense transcript of SSTR5-ASI ( Pedraza-Arevalo et al 2022 ).…”