Long Noncoding RNA GAS5: A Novel Marker Involved in Glucocorticoid Response

Abstract

Glucocorticoids (GCs) exert their effects through regulation of gene expression after activation in the cytoplasm of the glucocorticoid receptor (GR) encoded by NR3C1 gene. A negative feedback mechanism resulting in GR autoregulation has been demonstrated through the binding of the activated receptor to intragenic sequences called GRE-like elements, contained in GR gene. The long noncoding RNA growth arrest-specific transcript 5 (GAS5) interacts with the activated GR suppressing its transcriptional activity. The aim of this study was to evaluate the possible role of GAS5 and NR3C1 gene expression in the antiproliferative effect of methylprednisolone in peripheral blood mononuclear cells and to correlate the expression with individual sensitivity to GCs. Subjects being poor responders to GCs presented higher levels of GAS5 and NR3C1 in comparison with good responders. We suggest that abnormal levels of GAS5 may alter GC effectiveness, probably interfering with the mechanism of GR autoregulation.

Role of the Long Non‐Coding RNA Growth Arrest‐Specific 5 in Glucocorticoid Response in Children with Inflammatory Bowel Disease

“…Our studies revealed that, in untreated cell lines, no difference was evident in GAS5 levels between the two cell lines; as already demonstrated in our laboratory in PBMCs [17,18], suggesting therefore that the levels of GAS5 cannot predict the response to GCs in advance.…”

“…It has been already reported that the up-regulation of GAS5 occurring in PBMCs from poor responders after treatment with MP could prevent the activated GR from binding to GRE elements [17,18]. The present data suggest that, even in LoVo cells, which are resistant to GCs, higher levels of GAS5 may alter GC effectiveness through the inhibition of their activity by inhibiting the binding of the activated GR to GREs.…”

“…Recent investigations in this field were conducted in our laboratory: in particular, we have demonstrated a correlation between the lncRNA GAS5 levels and the sensitivity to GCs in vitro [17,18]. In this report, we analysed the role of GAS5 in modulating GC response on HeLa and LoVo cell lines, which endogenously express the GR and the lncRNA GAS5.…”

“…In poor responders, higher levels of GAS5 were evident in comparison with good responders, suggesting that this lncRNA could be involved in GC resistance [17,18]. The current investigation was therefore stimulated by the demonstration of the key role played by GAS5 in modulating GC response.…”

Novel insights into the molecular mechanisms underlying generalized glucocorticoid resistance and hypersensitivity syndromes

“…Lucafo et al demonstrated that poor responders to glucocorticoids had increased levels of GAS5 compared to good responders. 106 These accumulating data evidence the fact that novel technologies, including whole-genome sequencing, whole-exome sequencing and RNA sequencing, will undoubtedly enable us to acquire a deeper understanding of the GR "interactome". …”