Expression and DNA methylation of 20S proteasome subunits as prognostic and resistance markers in cancer.

Proteasomes are involved in the maintenance of cellular protein homeostasis and the control of numerous cellular pathways. Single proteasome genes or subunits have been identified as important players in cancer development and progression without considering the proteasome as a multisubunit protease. We here conducted a comprehensive pan-cancer analysis encompassing transcriptional, epigenetic, mutational landscapes, pathway enrichments, and survival outcomes linked to the 20S proteasome core complex. The impact of proteasome gene expression on patient survival exhibited a cancer type-dependent pattern. Increased proteasome expression correlated with elevated activation of oncogenic pathways, such as DNA repair, MYC-controlled gene networks, MTORC1 signalling, oxidative phosphorylation, as well as metabolic pathways including glycolysis and fatty acid metabolism. Accordingly, potential loss of function variants of proteasome subunit genes are associated with improved patient survival. The TCGA-derived outcomes were further supported by gene expression analysis of THP-1 cells. Our study highlighted the importance of studying the proteasome as an enzymatic functional unit rather than separated subunits.