التفاصيل البيبلوغرافية
| العنوان: |
Transcription Factor ASCL1 Acts as a Novel Potential Therapeutic Target for the Treatment of the Cushing’s Disease. |
| المؤلفون: |
Zhengyuan Chen, Qi Jia, Zhaozhao Zhao, Qilin Zhang, Yu Chen, Nidan Qiao, Zhao Ye, Chenxing Ji, Yichao Zhang, Wenqiang He, Chengzhang Shi, Yixin Cai, Boyuan Yao, Rui Han, Ye Wang, Xuefei Shou, Ming Shen, Xiaoyun Cao, Xiang Zhou, Haixia Cheng |
| المصدر: |
Journal of Clinical Endocrinology & Metabolism; Aug2022, Vol. 107 Issue 8, p2296-2306, 11p |
| مصطلحات موضوعية: |
TRANSCRIPTION factors, CUSHING'S syndrome treatment |
| مستخلص: |
Background: The pathogenesis of Cushing’s disease (CD) is still not adequately understood despite the identification of somatic driver mutations in USP8, BRAF, and USP48. In this multiomics study, we combined RNA sequencing (RNA-seq) with Sanger sequencing to depict transcriptional dysregulation under different gene mutation backgrounds. Furthermore, we evaluated the potential of achaete-scute complex homolog 1 (ASCL1), a pioneer transcription factor, as a novel therapeutic target for treatment of CD and its possible downstream pathway. Methods: RNA-seq was adopted to investigate the gene expression profile of CD, and Sanger sequencing was adopted to detect gene mutations. Bioinformatics analysis was used to depict transcriptional dysregulation under different gene mutation backgrounds. The function of ASCL1 in hormone secretion, cell proliferation, and apoptosis were studied in vitro. The effectiveness of an ASCL1 inhibitor was evaluated in primary CD cells, and the clinical relevance of ASCL1 was examined in 68 patients with CD. RNA-seq in AtT-20 cells on Ascl1 knockdown combined with published chromatin immunoprecipitation sequencing data and dual luciferase assays were used to explore downstream pathways. Results: ASCL1 was exclusively overexpressed in USP8-mutant and wild-type tumors. Ascl1 promoted adrenocorticotrophin hormone overproduction and tumorigenesis and directly regulated Pomc in AtT-20 cells. An ASCL1 inhibitor presented promising efficacy in both AtT-20 and primary CD cells. ASCL1 overexpression was associated with a larger tumor volume and higher adrenocorticotrophin secretion in patients with CD. Conclusion: Our findings help to clarify the pathogenesis of CD and suggest that ASCL1 is a potential therapeutic target the treatment of CD. [ABSTRACT FROM AUTHOR] |
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| قاعدة البيانات: |
Complementary Index |
