摘要：SummaryThe proteasome is a therapeutic target in cancer, but resistance to proteasome inhibitors often develops owing to the induction of compensatory pathways. Through a genome-wide siRNA screen combined with RNA sequencing analysis, we identified hexokinase and downstream O-GlcNAcylation as cell survival factors under proteasome impairment. The inhibition of O-GlcNAcylation synergistically induced massive cell death in combination with proteasome inhibition. We further demonstrated that O-GlcNAcylation was indispensable for maintaining proteasome activity by enhancing biogenesis as well as proteasome degradation in a manner independent of Nrf1, a well-known compensatory transcription factor that upregulates proteasome gene expression. Our results identify a pathway that maintains proteasome function under proteasome impairment, providing potential targets for cancer therapy.Graphical AbstractDisplay OmittedHighlights•O-GlcNAcylation suppresses cell death under proteasome impairment•Combined inhibition of O-GlcNAcylation and proteasome induces massive tumor cell death•O-GlcNAcylation maintains proteasome activity independently of Nrf1•O-GlcNAcylation enhances proteasome turnover under the proteasome impairmentBiological Sciences; Cell Biology; Functional Aspects of Cell Biology; Cancer
