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

Abstract

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 multi-subunit protease. We here conduct 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 exhibits a cancer-type dependent pattern. Escalated proteasome expression associates with elevated activation of oncogenic pathways, such as DNA repair, MYC- controlled gene networks, MTORC1 signaling, oxidative phosphorylation, as well as metabolic pathways including glycolysis and fatty acid metabolism. Vice versa, potential loss of function variants correlates with improved survival. The TCGA-derived outcomes are further supported by gene expression analysis of THP-1 cells. Our study reframes these subunits as an integrated functional ensemble, rather than separated subunits.Abstract Figure