Ubiquitin-Specific Protease 8 Mutant Corticotrope Adenomas Present Unique Secretory and Molecular Features and Shed Light on the Role of Ubiquitylation on ACTH Processing.

Somatic mutations in the ubiquitin-specific protease 8 (USP8) gene have recently been shown to occur in ACTH-secreting pituitary adenomas, thus calling attention to the ubiquitin system in corticotrope adenomas. Assess the consequences of USP8 mutations and establish the role of ubiquitin on ACTH turnover in human ACTH-secreting pituitary adenomas. USP8 mutation status was established in 126 ACTH-secreting adenomas. Differences in ACTH secretion and POMC expression from adenoma primary cultures and in microarray gene expression profiles from archival specimens were sought according to USP8 sequence. Ubiquitin/ACTH coimmunoprecipitation and incubation with MG132, a proteasome inhibitor, were performed in order to establish whether ubiquitin plays a role in POMC/ACTH degradation in corticotrope adenomas. USP8 mutations were identified in 29 adenomas (23%). Adenomas presenting USP8 mutations secreted greater amounts of ACTH and expressed POMC at higher levels compared to USP wild-type specimens. USP8 mutant adenomas were also more sensitive to modulation by CRH and dexamethasone in vitro. At microarray analysis, genes associated with endosomal protein degradation and membrane components were downregulated in USP8 mutant adenomas as were AVPR1B, IL11RA, and PITX2. Inhibition of the ubiquitin-proteasome pathway increased ACTH secretion and POMC itself proved a target of ubiquitylation, independently of USP8 sequence status. Our study has shown that USP8 mutant ACTH-secreting adenomas present a more "typical" corticotrope phenotype and reduced expression of several genes associated with protein degradation. Further, ubiquitylation is directly involved in intracellular ACTH turnover, suggesting that the ubiquitin-proteasome system may represent a target for treatment of human ACTH-secreting adenomas.

Sesta A ，Cassarino MF ，Terreni M ，Ambrogio AG ，Libera L ，Bardelli D ，Lasio G ，Losa M ，Pecori Giraldi F ... -  《-》

The Gene of the Ubiquitin-Specific Protease 8 Is Frequently Mutated in Adenomas Causing Cushing's Disease.

Perez-Rivas LG ，Theodoropoulou M ，Ferraù F ，Nusser C ，Kawaguchi K ，Stratakis CA ，Faucz FR ，Wildemberg LE ，Assié G ，Beschorner R ，Dimopoulou C ，Buchfelder M ，Popovic V ，Berr CM ，Tóth M ，Ardisasmita AI ，Honegger J ，Bertherat J ，Gadelha MR ，Beuschlein F ，Stalla G ，Komada M ，Korbonits M ，Reincke M ... -  《-》

The USP8 mutational status may predict drug susceptibility in corticotroph adenomas of Cushing's disease.

Somatic mutations in the ubiquitin-specific peptidase USP8 gene were recently detected in one- to two-third(s) of corticotroph adenomas of Cushing's disease (CD). These mutations may lead to the deubiquitination of EGFR, thereby increasing EGFR signaling, which has been implicated in ACTH hypersecretion. Our objective was to determine the impact of USP8 mutations on the clinicopathological features of CD. USP8 mutations as well as clinicopathological characteristics were examined in 60 corticotroph adenomas including 15 Crooke's cell adenomas (CCAs), a rare histological variant presenting with generally aggressive behavior, using qRT-PCR and/or immunohistochemistry. USP8 mutations were exclusively detected in women, except for one case, with a prevalence of 42.2% in non-CCA and 13.3% in CCA (overall 35%). Clinically well-behaved presentations including microadenoma and curative resection were more common in mutated cases. The expression of EGFR was not associated with the mutation status. In contrast, mutated tumors expressed significantly higher levels of POMC, SSTR5, and MGMT. Microadenomas that strongly express POMC were common among mutated tumors, which may lead to the mechanisms by which very small adenomas secrete excess ACTH to present overt CD. While USP8 mutations were less likely to enhance tumorous ACTH hypersecretion via EGFR-mediated activation, the presence of USP8 mutations may predict favorable responses to the somatostatin analog pasireotide, which exhibits high affinity for SSTR5. In contrast, non-mutated aggressive tumors such as CCA may respond better to the alkylating agent temozolomide because of their significantly weak expression of MGMT.

Hayashi K ，Inoshita N ，Kawaguchi K ，Ibrahim Ardisasmita A ，Suzuki H ，Fukuhara N ，Okada M ，Nishioka H ，Takeuchi Y ，Komada M ，Takeshita A ，Yamada S ... -  《-》

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

Ma ZY ，Song ZJ ，Chen JH ，Wang YF ，Li SQ ，Zhou LF ，Mao Y ，Li YM ，Hu RG ，Zhang ZY ，Ye HY ，Shen M ，Shou XF ，Li ZQ ，Peng H ，Wang QZ ，Zhou DZ ，Qin XL ，Ji J ，Zheng J ，Chen H ，Wang Y ，Geng DY ，Tang WJ ，Fu CW ，Shi ZF ，Zhang YC ，Ye Z ，He WQ ，Zhang QL ，Tang QS ，Xie R ，Shen JW ，Wen ZJ ，Zhou J ，Wang T ，Huang S ，Qiu HJ ，Qiao ND ，Zhang Y ，Pan L ，Bao WM ，Liu YC ，Huang CX ，Shi YY ，Zhao Y ... -  《-》

Clinical characteristics and surgical outcome in USP8-mutated human adrenocorticotropic hormone-secreting pituitary adenomas.

Losa M ，Mortini P ，Pagnano A ，Detomas M ，Cassarino MF ，Pecori Giraldi F ... -  《-》