2. Academic Validation
  3. Transcription Factor ASCL1 Acts as a Novel Potential Therapeutic Target for the Treatment of the Cushing's Disease

Transcription Factor ASCL1 Acts as a Novel Potential Therapeutic Target for the Treatment of the Cushing's Disease

  • J Clin Endocrinol Metab. 2022 Jul 14;107(8):2296-2306. doi: 10.1210/clinem/dgac280.
Zhengyuan Chen 1 2 3 4 5,  Qi Jia 6,  Zhaozhao Zhao 6,  Qilin Zhang 1 2 3 4 5,  Yu Chen 6,  Nidan Qiao 1 2 3 4 5,  Zhao Ye 1 2 3 4 5,  Chenxing Ji 1 2 3 4,  Yichao Zhang 1 2 3 4 5,  Wenqiang He 1 2 3 4 5,  Chengzhang Shi 1 2 3 4 5,  Yixin Cai 1 2 3 4,  Boyuan Yao 1 2 3 4,  Rui Han 1 2 3 4,  Ye Wang 1 2 3 4,  Xuefei Shou 1 2 3 4 5,  Ming Shen 1 2 3 4 5,  Xiaoyun Cao 1 2 3 4 5,  Xiang Zhou 1 2 3 4 5,  Haixia Cheng 7,  Jingjing Zhu 7,  Yao Hu 8,  Zhaoyun Zhang 9,  Hongying Ye 9,  Yiming Li 9,  Shiqi Li 1 2 3 4 5,  Yongfei Wang 1 2 3 4 5,  Zengyi Ma 1 2 3 4 5,  Ting Ni 10,  Yao Zhao 1 2 3 4 5 11 12 13
Affiliations

Affiliations

  • 1 Department of Neurosurgery, Huashan Hospital, Fudan University, Shanghai, China.
  • 2 Neurosurgical Institute of Fudan University, Shanghai, China.
  • 3 Shanghai Clinical Medical Center of Neurosurgery, Shanghai, China.
  • 4 Shanghai Key Laboratory of Brain Function Restoration and Neural Regeneration, Shanghai, China.
  • 5 Shanghai Pituitary Tumor Center, Shanghai,, China.
  • 6 State Key Laboratory of Genetic Engineering, Collaborative Innovation Center of Genetics and Development, Human Phenome Institute, School of Life Sciences and Huashan Hospital, Fudan University, Shanghai 200438, China.
  • 7 Department of Pathology, Huashan Hospital, Fudan University, Shanghai, China.
  • 8 Department of Laboratory Medicine, Huashan Hospital, Fudan University, Shanghai, China.
  • 9 Department of Endocrinology and Metabolism, Huashan Hospital, Fudan University, Shanghai, China.
  • 10 State Key Laboratory of Genetic Engineering, Collaborative Innovation Center of Genetics and Development, Human Phenome Institute, School of Life Sciences and Huashan Hospital, Fudan University, Shanghai, China.
  • 11 State Key Laboratory of Medical Neurobiology and MOE Frontiers Center for Brain Science, Institutes of Brain Science, Fudan University, Shanghai, China.
  • 12 National Clinical Research Center for Aging and Medicine, Huashan Hospital, Fudan University, Shanghai, Shanghai, China.
  • 13 National Center for Neurological Disorders, Huashan Hospital, Fudan University, 201100, China.
PMID: 35521682 DOI: 10.1210/clinem/dgac280
Abstract

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.

Summary: The pathogenesis of Cushing's disease (CD) is still not adequately understood despite the identification of somatic driver mutations in USP8, BRaf, and USP48. Moreover, few effective medical therapies are currently available for the treatment of CD. Here, using a multiomics approach, we first report the aberrant overexpression of the transcription factor gene ASCL1 in USP8-mutant and wild-type tumors of CD. Ascl1 promoted adrenocorticotrophin hormone overproduction and tumorigenesis and directly regulated Pomc in mouse AtT-20 cells. Notably, an ASCL1 inhibitor presented promising efficacy in both AtT-20 and primary CD cells. Importantly, ASCL1 overexpression was associated with a larger tumor volume and higher adrenocorticotrophin secretion in patients with CD. Thus, our findings improve understanding of CD pathogenesis and suggest that ASCL1 is a potential therapeutic target the treatment of CD.

Keywords

ASCL1; Cushing’s disease; therapeutic target; transcriptional dysregulation.

Figures
Products