ACTH oversecretion in USP8-mutated adenomas may also be explained by the fact that USP8 hyperactivation may directly cause a reduction in POMC and POMC precursors of ubiquitin-mediated degradation; conversely, ACTH is not a target of ubiquitylation as it is synthetized outside the endoplasmic reticulum: its increased secretion in USP8-mutated adenomas appears then to be a consequence of increased EGF signaling and POMC production, as shown in corticotrope adenoma primary cultures [15]. This evidence concerns the gene USP8 and adenoma.