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Recurrent gain-of-function USP8 mutations in Cushing's disease
Zeng-Yi Ma1, Zhi-Jian Song2, Jian-Hua Chen3
1Department of Neurosurgery, Shanghai Pituitary Tumor Center, Huashan Hospital, Shanghai Medical College, Fudan University, Shanghai 200040, China.
Cell Research
|February 14, 2015
Summary
Somatic USP8 mutations are common in Cushing's disease, driving excess ACTH production. Targeting USP8 or EGFR offers a promising therapeutic strategy for these pituitary tumors.
Area of Science:
- Endocrinology
- Molecular Biology
- Oncology
Background:
- Cushing's disease results from excess cortisol production, often due to ACTH-secreting pituitary adenomas.
- Genetic causes of ACTH-secreting pituitary adenomas remain largely unknown.
- Understanding the genetic landscape is crucial for targeted therapies.
Purpose of the Study:
- To identify genetic alterations in ACTH-secreting pituitary adenomas.
- To investigate the role of USP8 mutations in Cushing's disease pathogenesis.
- To explore potential therapeutic targets for USP8-mutated tumors.
Main Methods:
- Whole-exome sequencing of 12 ACTH-secreting pituitary adenomas and matched blood samples.
- Sanger and targeted sequencing of USP8 in 258 additional pituitary adenomas.
- Functional assays assessing USP8-EGFR interaction and ACTH secretion.
Main Results:
- Somatic USP8 mutations were identified exclusively in exon 14 of ACTH-secreting pituitary adenomas (62.04% in 108 cases).
- These mutations disrupt USP8 binding to 14-3-3 protein, increasing EGFR stability and POMC expression.
- USP8-mutated tumors showed smaller size but higher ACTH production compared to wild-type.
- USP8 knockdown or EGFR inhibition reduced ACTH secretion in vitro.
Conclusions:
- Somatic gain-of-function USP8 mutations are a frequent driver of ACTH overproduction in Cushing's disease.
- USP8 and EGFR represent potential therapeutic targets for corticotrophin adenomas.
- This study elucidates key genetic mechanisms and therapeutic avenues for Cushing's disease.
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