<i>O</i>-GlcNAcylation Signal Mediates Proteasome Inhibitor Resistance in Cancer Cells by Stabilizing NRF1

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  • Hiroki Sekine
    Department of Gene Expression Regulation, Institute of Development, Aging and Cancer, Tohoku University, Sendai, Japan
  • Keito Okazaki
    Department of Gene Expression Regulation, Institute of Development, Aging and Cancer, Tohoku University, Sendai, Japan
  • Koichiro Kato
    Division of Oxygen Biology, Tohoku University Graduate School of Medicine, Sendai, Japan
  • M. Morshedul Alam
    Department of Gene Expression Regulation, Institute of Development, Aging and Cancer, Tohoku University, Sendai, Japan
  • Hiroki Shima
    Department of Biochemistry, Tohoku University Graduate School of Medicine, Sendai, Japan
  • Fumiki Katsuoka
    Department of Medical Biochemistry, Tohoku University Graduate School of Medicine, Sendai, Japan
  • Tadayuki Tsujita
    Department of Integrative Genomics, Tohoku Medical Megabank Organization, Tohoku University, Sendai, Japan
  • Norio Suzuki
    Division of Oxygen Biology, Tohoku University Graduate School of Medicine, Sendai, Japan
  • Akira Kobayashi
    Laboratory of Biochemistry, Department of Applied Biochemistry and Food Science, Faculty of Agriculture, Saga University, Saga, Japan
  • Kazuhiko Igarashi
    Department of Biochemistry, Tohoku University Graduate School of Medicine, Sendai, Japan
  • Masayuki Yamamoto
    Laboratory for Genetic Code, Graduate School of Life and Medical Sciences, Doshisha University, Kyotanabe, Kyoto, Japan
  • Hozumi Motohashi
    Department of Gene Expression Regulation, Institute of Development, Aging and Cancer, Tohoku University, Sendai, Japan

説明

Cancer cells often heavily depend on the ubiquitin-proteasome system (UPS) for their growth and survival. Irrespective of their strong dependence on the proteasome activity, cancer cells, except for multiple myeloma, are mostly resistant to proteasome inhibitors. A major cause of this resistance is the proteasome bounce-back response mediated by NRF1, a transcription factor that coordinately activates proteasome subunit genes. To identify new targets for efficient suppression of UPS, we explored, using immunoprecipitation and mass spectrometry, the possible existence of nuclear proteins that cooperate with NRF1 and identified O-linked N-acetylglucosamine transferase (OGT) and host cell factor C1 (HCF-1) as two proteins capable of forming a complex with NRF1. O-GlcNAcylation catalyzed by OGT was essential for NRF1 stabilization and consequent upregulation of proteasome subunit genes. Meta-analysis of breast and colorectal cancers revealed positive correlations in the relative protein abundance of OGT and proteasome subunits. OGT inhibition was effective at sensitizing cancer cells to a proteasome inhibitor both in culture cells and a xenograft mouse model. Since active O-GlcNAcylation is a feature of cancer metabolism, our study has clarified a novel linkage between cancer metabolism and UPS function and added a new regulatory axis to the regulation of the proteasome activity.

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