ASCL1 a potential therapeutic target for treating Cushing’s disease

20 Aug 2022
ASCL1 a potential therapeutic target for treating Cushing’s disease

A recent study attempting to understand the pathogenesis of Cushing’s disease (CD) suggests the potential of achaete-scute complex homolog 1 (ASCL1), a pioneer transcription factor, as a therapeutic target for the treatment of CD.

“The pathogenesis of CD is still not adequately understood despite the identification of somatic driver mutations in USP8BRAF, and USP48,” the researchers noted.

To address this gap in understanding, a multiomics analysis was conducted. The researchers adopted RNA sequencing to examine the gene expression profile of CD and Sanger sequencing to detect gene mutations. They also performed bioinformatics analysis to illustrate transcriptional dysregulation under different gene mutation backgrounds.

The function of ASCL1 in hormone secretion, cell proliferation, and apoptosis were studied in vitro. In addition, the researchers assessed the effectiveness of an ASCL1 inhibitor in primary CD cells, as well as the clinical relevance of ASCL1 in 68 patients with CD.

Finally, downstream pathways were explored using RNA sequencing in AtT-20 cells on ASCL1 knockdown combined with published chromatin immunoprecipitation sequencing data and dual luciferase assays.

An exclusive overexpression of ASCL1 was observed in USP8-mutant and wild-type tumours. ASCL1 induced adrenocorticotrophin hormone overproduction and tumorigenesis. It also directly regulated Pomc in AtT-20 cells.

Notably, an ASCL1 inhibitor demonstrated its potential efficacy in both AtT-20 and primary CD cells. Furthermore, ASCL1 overexpression appeared to contribute to a larger tumour volume and higher adrenocorticoptrophin secretion in patients with CD.

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