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Compound-induced NR5A1 circular RNA and aberrant multiple exon-skipping attenuate aberrant steroidogenesis

ABSTRACT: Despite the intensive search for an effective drug to ameliorate excess steroid production, there are few pharmacological options, especially for diseases as steroid-producing adrenocortical cancers. While splice-modifying-compounds have pleiotropic effects including anticancer properties, none have been tested on abnormal steroidogenesis. Using H295R adrenocortical carcinoma cells, CX-4945 induced multiple exon skipping of the NR5A1 gene, the master regulator of steroidogenesis. The resulting exon-skipped NR5A1 proteins were non-functional when added-back to NR5A1 knocked down H295R cells. This eventually suppressed steroidogenesis and induced dysfunctional autophagy with progression to ER-stress-related apoptosis. Intriguingly, a circular RNA of NR5A1 exons (circNR5A1 ex2-4 RNA) not originating from the skipped exons, was induced. Transient expression of this circNR5A1 ex2-4 RNA induced the same multiple exon-skipped isoforms of the NR5A1 gene. This potential pharmacological control of NR5A1 aberrant multiple exon-skipping and interplay with its circNR5A1 RNA gives us a novel target for treating abnormal steroidogenesis in adrenocortical carcinomas.

ORGANISM(S): Homo sapiens

PROVIDER: GSE133197 | GEO | 2022/06/24

REPOSITORIES: GEO

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Compound-induced NR5A1 exon-skipping and circular-RNA expression show impaired steroidogenesis in adrenocortical cancer cells

Project description:Despite the intensive search for an effective drug to treat steroid-producing adrenocortical carcinomas, there are few therapeutic options. We sought whether splicing modifying compounds are effective on this devastating disease. Here, we show that a chemical compound in clinical trial, CX-4945, suppressed the expression of NR5A1 through aberrant multiple exon skipping leading to suppressed steroidogenesis and induced dysfunctional autophagy and progression to ER-stress-related apoptosis. A circular RNA of NR5A1 exons with an IRE1α-cleavage site on the ligated ends (circAd4BP HAC1-type ex1-6 RNA) is expressed in normal adrenal cortex but not in H295R adrenocortical cancer cells, and CX-4945 induced a different circular RNA of NR5A1 exons (circAd4BP ex2-4 RNA). This potential pharmacological control of abnormal steroidogenesis through NR5A1 aberrant splicing and interplay with its circAd4BP makes CX-4945 a strong candidate novel drug for the treatment of adrenocortical carcinomas.

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Compound-induced NR5A1 circular RNA and aberrant multiple exon-skipping attenuate aberrant steroidogenesis

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Project description:Androgens are essential for sexual development and reproduction. However, androgen regulation in health and disease is poorly understood. Previously, we showed that human adrenocortical H295R cells grown under starvation conditions acquire a hyperandrogenic steroid profile with changes in steroid metabolizing enzymes HSD3B2 and CYP17A1 essential for androgen production. Furthermore, we have shown that metformin inhibits androgen production of steroidogenic H295R cells and inhibits complex I activity of the respriatory chain. Therefore, to search for underlying mechanisms regulting androgen production and to understand the basic biology of androgens, we have characterized the gene expression profile of H295R cells grown under normal growth conditions, serum starvation (hyperandrogenic) growth conditions as well as after metformin treatment (hypoandrogenic). In this dataset, we first characterized the gene expression profile of H295R cells cultured under nromal growth vs serum-starved (hypernadrogenic) growth conditions. Expression profiling of starved H295R cells revealed alterations in genes involved in steroid and energy metabolism and signal transduction. We discovered two new gene networks around RARB and ANGPTL1, and show how they regulate androgen biosynthesis (Udhane SS et al.,2015). In a second part, we compared the gene expression profile of H295R cells grown under serum starvation (hyperandrogenic) conditions to metformin treated (hypoandrogenic) cells in search for the underlying androgen regulating network. (Udhane et al., manuscript in preparation).

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