Medical School
Twin Cities
Cushing’s disease (CD) is caused by a corticotroph adenoma in the anterior pituitary. Overexpression of the POMC (proopiomelanocortin) gene, which encodes a peptide precursor of adrenocorticotropic hormone (ACTH), leads to oversecretion of ACTH, and, in turn, of cortisol from the adrenal glands. Hypercortisolemia in CD predisposes patients to a wide variety of serious comorbid disorders, and can be fatal without propertreatment in timely manner. CD is 4-6–fold more prevalent in females than in males, and its occurrence peaks during reproductive years; however, the mechanisms underlying female predominance remain unknown.
This project tests the group's hypothesis that gain-of-function mutations in ubiquitin-specific protease 8 (USP8) underlie female-biased CD by signaling through the X-linked androgen receptor (AR). USP8 is a member of a large family of deubiquitinases that can remove conjugated ubiquitin from proteins, playing an important regulatory role in preventing protein degradation. Gain-of-function somatic point mutations of the USP8 gene have been found in 30-50% of examined CD tumors, and USP8-mutation-positive CD is 8-20 times more common in females than in males. The central hypothesis is that gain-of-function USP8 mutations promote the development of female-biased CD by signaling through AR. Preliminary data collectively support this hypothesis:
- UPS8 is localized in the nucleus in USP8-mutated CD
- USP8 can deubiquitinate AR
- AR nuclear accumulation, which is higher in female than in male CD, is even more enhanced in USP8-mutated CD
- Wxpression of AR and its target genes is upregulated in CD tumors and in USP8-mutated CD.
The researchers also found that AR promoter is more de-methylated in female CD than in male CD, indicating epigenetic regulation of AR in CD tumors. In order to test whether USP8 mutations drive CD tumorigenesis, the researchers successfully generated human pluripotent stem cell (PSCs)-derived pituitary corticotroph organoids with inducible expression of wild-type or mutated USP8. These innovative approaches, including transcriptome profiling of normal corticotrophs and CD by the spatial genomics technology and 3-dimentional human pituitary organoid systems, will lead to elucidation of a long-standing question in the field: mechanisms of female-biased occurrence of CD. Moreover, the human pituitary organoid approach will test novel CD treatment options, which may potentially identify sex-specific therapeutic targets.