PA28γ promotes the malignant progression of tumor by elevating mitochondrial function via C1QBP

Abstract

Proteasome activator 28gamma (PA28gamma) plays a critical role in malignant progression of various tumors, however, its role and regulation are not well understood. Here, using oral squamous cell carcinoma (OSCC) as main research model, we discovered that PA28gamma interacted with complement 1q binding protein (C1QBP), which is dependent on the N-terminus of C1QBP rather than the known functional domain (amino acids 168-213). Notably, we found that PA28gamma can enhance C1QBP protein stability in OSCC. Functionally, PA28gamma contributes to the malignant progression of OSCC by affecting mitochondrial morphology and oxidative phosphorylation (OXPHOS) through C1QBP in vitro and vivo. Mechanically, PA28gamma upregulate the expression of optic atrophy 1 (OPA1), mitofusin 2 (MFN1), mitofusin 2 (MFN2) and the mitochondrial respiratory complex by C1QBP. Moreover, in a clinical cohort of OSCC patients, PA28gamma was positively correlated with C1QBP expression and negatively correlated with prognosis. Therefore, C1QBP is also a potential target for the treatment and prognosis of cancer.