Recurrent gain-of-function USP8 mutations in Cushing's disease

被引：259

作者：

Ma, Zeng-Yi ^{[1
]}

Song, Zhi-Jian ^{[2
]}

Chen, Jian-Hua ^{[2
,3
]}

Wang, Yong-Fei ^{[1
]}

Li, Shi-Qi ^{[1
]}

Zhou, Liang-Fu ^{[1
]}

Mao, Ying ^{[1
]}

Li, Yi-Ming ^{[4
]}

Hu, Rong-Gui ^{[5
]}

Zhang, Zhao-Yun ^{[4
]}

Ye, Hong-Ying ^{[4
]}

Shen, Ming ^{[1
]}

Shou, Xue-Fei ^{[1
]}

Li, Zhi-Qiang ^{[2
]}

Peng, Hong ^{[5
]}

Wang, Qing-Zhong ^{[2
]}

Zhou, Dai-Zhan ^{[2
]}

Qin, Xiao-Lan ^{[2
]}

Ji, Jue ^{[2
]}

Zheng, Jie ^{[2
]}

Chen, Hong ^{[6
]}

Wang, Yin ^{[6
]}

Geng, Dao-Ying ^{[7
]}

Tang, Wei-Jun ^{[7
]}

Fu, Chao-Wei ^{[8
]}

Shi, Zhi-Feng ^{[1
]}

Zhang, Yi-Chao ^{[1
]}

Ye, Zhao ^{[1
]}

He, Wen-Qiang ^{[1
]}

Zhang, Qi-Lin ^{[1
]}

Tang, Qi-Sheng ^{[1
]}

Xie, Rong ^{[1
]}

Shen, Jia-Wei ^{[2
]}

Wen, Zu-Jia ^{[2
]}

Zhou, Juan ^{[2
]}

Wang, Tao ^{[9
]}

Huang, Shan ^{[9
]}

Qiu, Hui-Jia ^{[1
]}

Qiao, Ni-Dan ^{[1
]}

Zhang, Yi ^{[1
]}

Pan, Li ^{[1
]}

Bao, Wei-Min ^{[1
]}

Liu, Ying-Chao ^{[10
]}

Huang, Chuan-Xin ^{[11
,12
]}

Shi, Yong-Yong ^{[2
,13
]}

Zhao, Yao ^{[1
]}

机构：

[1] Fudan Univ, Shanghai Med Coll, Huashan Hosp, Dept Neurosurg,Shanghai Pituitary Tumor Ctr, Shanghai 200040, Peoples R China

[2] Shanghai Jiao Tong Univ, Inst Social Cognit & Behav Sci, Key Lab Genet Dev & Neuropsychiat Disorders, BioX Inst,Minist Educ, Shanghai 200030, Peoples R China

[3] Shanghai Jiao Tong Univ, Shanghai Mental Hlth Ctr, Shanghai Key Lab Psychot Disorders, Sch Med, Shanghai 200030, Peoples R China

[4] Fudan Univ, Shanghai Med Coll, Huashan Hosp, Dept Endocrinol, Shanghai 200040, Peoples R China

[5] Chinese Acad Sci, Inst Biochem & Cell Biol, Shanghai Inst Biol Sci, State Key Lab Mol Biol, Shanghai 200031, Peoples R China

[6] Fudan Univ, Shanghai Med Coll, Huashan Hosp, Dept Neuropathol, Shanghai 200040, Peoples R China

[7] Fudan Univ, Shanghai Med Coll, Huashan Hosp, Dept Radiol, Shanghai 200040, Peoples R China

[8] Fudan Univ, Sch Publ Hlth, Dept Epidemiol, Shanghai 200032, Peoples R China

[9] Shanghai 5th Peoples Hosp, Dept Neurosurg, Shanghai 200240, Peoples R China

[10] Shandong Univ, Prov Hosp, Dept Neurosurg, Jinan 250021, Shandong, Peoples R China

[11] Shanghai Jiao Tong Univ, Sch Med, Shanghai Inst Immunol, Shanghai 200025, Peoples R China

[12] Shanghai Jiao Tong Univ, Sch Med, Dept Immunobiol & Microbiol, Shanghai 200025, Peoples R China

[13] Qingdao Univ, Affiliated Hosp, Shandong Prov Key Lab Metab Dis, Qingdao 266003, Shandong, Peoples R China

来源：

CELL RESEARCH | 2015年 / 25卷 / 03期

基金：

国家高技术研究发展计划(863计划); 中国国家自然科学基金;

关键词：

Cushing's disease; pituitary adenomas; USP8; mutation; whole-exome sequencing; GROWTH-FACTOR RECEPTOR; SECRETING PITUITARY-ADENOMAS; GLUCOCORTICOID RESISTANCE; CORTICOTROPH ADENOMA; GERMLINE AIP; EXPRESSION; UBPY; GENE; TRAFFICKING; P27(KIP1);

D O I：

10.1038/cr.2015.20

中图分类号：

Q2 [细胞生物学];

学科分类号：

071009 ; 090102 ;

摘要：

Cushing's disease, also known as adrenocorticotropic hormone (ACTH)-secreting pituitary adenomas (PAs) that cause excess cortisol production, accounts for up to 85% of corticotrophin-dependent Cushing's syndrome cases. However, the genetic alterations in this disease are unclear. Here, we performed whole-exome sequencing of DNA derived from 12 ACTH-secreting PAs and matched blood samples, which revealed three types of somatic mutations in a candidate gene, USP8 (encoding ubiquitin-specific protease 8), exclusively in exon 14 in 8 of 12 ACTH-secreting PAs. We further evaluated somatic USP8 mutations in additional 258 PAs by Sanger sequencing. Targeted sequencing further identified a total of 17 types of USP8 variants in 67 of 108 ACTH-secreting PAs (62.04%). However, none of these mutations was detected in other types of PAs (n = 150). These mutations aggregate within the 14-3-3 binding motif of USP8 and disrupt the interaction between USP8 and 14-3-3 protein, resulting in an elevated capacity to protect EGFR from lysosomal degradation. Accordingly, PAs with mutated USP8 display a higher incidence of EGFR expression, elevated EGFR protein abundance and mRNA expression levels of POMC, which encodes the precursor of ACTH. PAs with mutated USP8 are significantly smaller in size and have higher ACTH production than wildtype PAs. In surgically resected primary USP8-mutated tumor cells, USP8 knockdown or blocking EGFR effectively attenuates ACTH secretion. Taken together, somatic gain-of-function USP8 mutations are common and contribute to ACTH overproduction in Cushing's disease. Inhibition of USP8 or EGFR is promising for treating USP8-mutated corticotrophin adenoma. Our study highlights the potentially functional mutated gene in Cushing's disease and provides insights into the therapeutics of this disease.

引用

页码：306 / 317

页数：12

共 37 条

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