Ubiquitination is reported to be a critical
biological event on
ACTH secretion in
corticotroph adenomas. However, the effect of ubiquitylation on
ACTH secretion in silent
corticotroph adenomas (SCAs) remains unclear. The aim of our study was to explore the mechanism of decreased secretion of
ACTH in SCAs with ubiquitinomics. The differently expressed
ubiquitinated proteins between SCAs and functioning
corticotroph adenomas (FCAs) were identified by 4D label-free mass spectrometer, followed by bioinformatics analysis. The function of the candidate ubiquitinated
protein ATP7A (K333) was validated in AtT20 cells. A total of 111 ubiquitinated sites corresponding to 94
ubiquitinated proteins were typically different between SCAs and FCAs. Among all the ubiquitinated sites, 102 showed decreased ubiquitination in SCAs, which mapped to 85
ubiquitinated proteins. Pathway enrichment analysis revealed that
ubiquitinated proteins were mainly enriched in vesicle pathway and
protein secretion pathway. ATP7A (K333) was one of the
proteins enriched in vesicle pathway and
protein secretion pathway with decreased ubiquitination level in SCAs. In vitro assay indicated that both ATP7A
siRNA and
omeprazole (
ATP7A protein inhibitor) increased the secretion of
ACTH in AtT20 cell supernatant compared to control groups (p<0.05). These results indicated that ATP7A might be related to the abnormal expression of
ACTH in SCAs and potential for the treatment of SCAs.