Background: Ubiquitination is a critical post-translational modification which can be reversed with an enzyme family known as deubiquitinating enzymes (DUBs). It has been reported that dysregulation of deubiquitination leads to carcinogenesis. As a member of the DUBs family, proteasome 26 S subunit non-ATPase 7 (PSMD7) serves as an underlying tumour-promoting factor in multiple cancers. However, the clinical significance and biological functions of PSMD7 in pancreatic cancer (PC) remain unclear.
Results: In this study, we first reported frequent overexpression of PSMD7 in PC tissues, and high levels of PSMD7 were markedly linked to shorter survival and a malignant phenotype in PC patients. An array of in vitro and in vivo gain/loss-of-function tests revealed that PSMD7 facilitates the progression of PC cells. Additionally, we found that PSMD7 promotes PC cell progression by activating the Notch homolog 1 (Notch1) signalling. Interestingly, in PC cells, the inhibitory effect of PSMD7 knockdown on cellular processes was comparable to that observed upon Notch1 knockdown. Mechanistically, PSMD7 deubiquitinated and stabilised sex determining region Y (SRY)-box 2 (SOX2), a key mediator of Notch1 signalling. The stabilisation of SOX2, mediated by PSMD7, dramatically increased SOX2 protein levels, subsequently activating the Notch1 pathway. Finally, restoration of SOX2 expression abrogated the PSMD7-silenced antitumour effect.
Conclusions: Taken together, our work identifies and validates PSMD7 as a promoter of PC progression through augmentation of the Notch1 signalling pathway mediated by SOX2. This finding suggests that PSMD7 holds promise as a potential therapeutic target for the management of this refractory disease.
Keywords: Notch1; PSMD7; Pancreatic cancer; Proliferation; SOX2.
© 2024. The Author(s).