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

Proteasome activator 28γ (PA28γ) 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 PA28γ 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 PA28γ enhances C1QBP protein stability in OSCC. Functionally, PA28γ contributes to the malignant progression of OSCC by affecting mitochondrial morphology and oxidative phosphorylation (OXPHOS) through C1QBP in vitro and vivo. Mechanically, PA28γ upregulates the expression of optic atrophy 1 (OPA1), mitofusin 1 (MFN1), mitofusin 2 (MFN2), and the mitochondrial respiratory complex via C1QBP. Moreover, in a clinical cohort of OSCC patients, PA28γ was positively correlated with C1QBP expression and negatively correlated with prognosis. Therefore, C1QBP represents a potential therapeutic target for cancer treatment and prognosis.