Phosphorylation of PA28γ by CK2 kinase facilitates HNSCC tumor formation and progression

Proteasome activator 28 subunit gamma (PA28γ) attracts considerable attention for its ability to regulate multiple molecules involved in tumor progression. However, its intrinsic activation and functional regulatory mechanisms in the regulation of tumor growth remain incompletely understood. Here, using head and neck squamous cell carcinoma (HNSCC) as a model, we identify phosphorylation at the T23 site of PA28γ, a modification that is highly expressed across pan-cancer types and associated with poor prognosis. Notably, phosphorylation-deficient PA28γ-T23 mutant mice exhibit resistance to carcinogen-induced HNSCC tumors, whereas the phosphomimetic PA28γ-T23 mutant promotes tumor formation and progression. We subsequently explore the underlying mechanism and find that casein kinase 2 (CK2) mediates PA28γ-T23 phosphorylation, which regulates the abundance of growth-related E4F transcription factor 1 (E4F1) through the PA28γ-proteasome pathway. These findings highlight PA28γ-T23 phosphorylation as a crucial pro-oncogenic signal and an unfavorable prognostic indicator across various cancers and underscore its potential as a target for early cancer intervention and treatment.