Responsiveness to DDAVP in Cushing's disease is associated with USP8 mutations through enhancing AVPR1B promoter activity.

Abstract

PURPOSE:

To clarify the characteristics of Cushing's disease (CD) patients who respond to the desmopressin (DDAVP) test and its underlying mechanisms.

METHODS:

Forty-seven patients with CD who underwent DDAVP testing were included. Patients were divided into two groups: DDAVP test (+) (adrenocorticotropic hormone [ACTH] levels increased by ≥ 1.5-fold during the DDAVP test) and DDAVP test (-) (ACTH levels increased by < 1.5-fold). AVP receptor expression levels in these tumors were quantified using quantitative RT-PCR and immunohistochemistry. AVP receptor promoter activity was analyzed using a dual-luciferase reporter assay system.

RESULTS:

Females (96.9%) and USP8 mutants (85.7%) were more prevalent in the DDAVP test (+) than in the DDAVP test (-). Indeed, the ACTH and cortisol responsiveness to DDAVP was greater in USP8 mutation positive tumors than that in USP8 wild type tumors (3.0-fold vs. 1.3-fold, 1.6-fold vs. 1.1-fold, respectively). Responsiveness to DDAVP was correlated with the expression levels of AVPR1B, but not with those of AVPR2. Comparably, Avpr1b promoter activity was enhanced by the overexpression of mutant USP8 compared to the wild type.

CONCLUSIONS:

We found that the responsiveness of ACTH to DDAVP in CD was greater in tumors with USP8 mutations. The present data suggest that USP8 mutations upregulate the AVPR1B promoter activity. Additionally, we showed that the DDAVP test can predict the presence of USP8 mutations.

• Authors: Hiroki Shichi, Hidenori Fukuoka, Maki Kanzawa, Masaaki Yamamoto, Naoki Yamamoto, Masaki Suzuki, Shin Urai, Ryusaku Matsumoto, Keitaro Kanie, Yasunori Fujita, Hironori Bando, Genzo Iguchi, Naoko Inoshita, Shozo Yamada, Yutaka Takahashi, Wataru Ogawa
• Journal: Pituitary (Pituitary) Vol. 25 Issue 3 Pg. 496-507 (Jun 2022) ISSN: 1573-7403 [Electronic] United States
• PMID: 35451730 (Publication Type: Journal Article)
• Copyright: © 2022. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.

Chemical References

• AVPR1b protein, human
• Endosomal Sorting Complexes Required for Transport
• Receptors, Vasopressin
• Adrenocorticotropic Hormone
• Endopeptidases
• USP8 protein, human
• Ubiquitin Thiolesterase
• Deamino Arginine Vasopressin
• Hydrocortisone

Topics

• Adrenocorticotropic Hormone (metabolism)
• Deamino Arginine Vasopressin (analysis, metabolism)
• Endopeptidases (genetics, metabolism)
• Endosomal Sorting Complexes Required for Transport (genetics, metabolism)
• Female
• Humans
• Hydrocortisone (metabolism)
• Mutation
• Pituitary ACTH Hypersecretion (genetics, metabolism)
• Promoter Regions, Genetic
• Receptors, Vasopressin (genetics)
• Ubiquitin Thiolesterase (genetics, metabolism)