文章基本信息

标题：Enhanced O-GlcNAcylation Mediates Cytoprotection under Proteasome Impairment by Promoting Proteasome Turnover in Cancer Cells
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作者：Eiichi Hashimoto ; Shota Okuno ; Shoshiro Hirayama 等
期刊名称：iScience
印刷版ISSN：2589-0042
出版年度：2020
卷号：23
期号：7
页码：1-33
DOI：10.1016/j.isci.2020.101299
语种：English
出版社：Elsevier
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