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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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