Enhanced O-GlcNAcylation Mediates Cytoprotection under Proteasome Impairment by Promoting Proteasome Turnover in Cancer Cells
Eiichi Hashimoto,
Shota Okuno,
Shoshiro Hirayama,
Yoshiyuki Arata,
Tsuyoshi Goto,
Hidetaka Kosako,
Jun Hamazaki,
Shigeo Murata
Affiliations
Eiichi Hashimoto
Laboratory of Protein Metabolism, Graduate School of Pharmaceutical Sciences, the University of Tokyo, Bunkyo-ku, Tokyo 1130033, Japan
Shota Okuno
Laboratory of Protein Metabolism, Graduate School of Pharmaceutical Sciences, the University of Tokyo, Bunkyo-ku, Tokyo 1130033, Japan
Shoshiro Hirayama
Laboratory of Protein Metabolism, Graduate School of Pharmaceutical Sciences, the University of Tokyo, Bunkyo-ku, Tokyo 1130033, Japan
Yoshiyuki Arata
Laboratory of Protein Metabolism, Graduate School of Pharmaceutical Sciences, the University of Tokyo, Bunkyo-ku, Tokyo 1130033, Japan
Tsuyoshi Goto
Laboratory of Protein Metabolism, Graduate School of Pharmaceutical Sciences, the University of Tokyo, Bunkyo-ku, Tokyo 1130033, Japan
Hidetaka Kosako
Division of Cell Signaling, Fujii Memorial Institute of Medical Sciences, Tokushima University, Kuramoto-cho, Tokushima 7708503, Japan
Jun Hamazaki
Laboratory of Protein Metabolism, Graduate School of Pharmaceutical Sciences, the University of Tokyo, Bunkyo-ku, Tokyo 1130033, Japan
Shigeo Murata
Laboratory of Protein Metabolism, Graduate School of Pharmaceutical Sciences, the University of Tokyo, Bunkyo-ku, Tokyo 1130033, Japan; Corresponding author
Summary: The 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.
