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NRF1 and NRF3 complementarily maintain a basal proteasome activity in cancer cells through CPEB3-mediated translational repression

Tsuyoshi Waku, Hiroyuki Katayama, Miyako Hiraoka, Atsushi Hatanaka, Nanami Nakamura, Yuya Tanaka, Natsuko Tamura, Akira Watanabe, Akira Kobayashi
doi: https://doi.org/10.1101/2020.01.10.902718
Tsuyoshi Waku
1Laboratory for Genetic Code, Department of Medical Life Systems, Faculty of Life and Medical Sciences, Doshisha University, Kyotanabe, Kyoto, Japan
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Hiroyuki Katayama
2Laboratory for Genetic Code, Graduate School of Life and Medical Sciences, Doshisha University, Kyotanabe, Kyoto, Japan
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Miyako Hiraoka
2Laboratory for Genetic Code, Graduate School of Life and Medical Sciences, Doshisha University, Kyotanabe, Kyoto, Japan
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Atsushi Hatanaka
2Laboratory for Genetic Code, Graduate School of Life and Medical Sciences, Doshisha University, Kyotanabe, Kyoto, Japan
3Research Fellow of Japan Society for the Promotion of Science, Tokyo, Japan
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Nanami Nakamura
2Laboratory for Genetic Code, Graduate School of Life and Medical Sciences, Doshisha University, Kyotanabe, Kyoto, Japan
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Yuya Tanaka
1Laboratory for Genetic Code, Department of Medical Life Systems, Faculty of Life and Medical Sciences, Doshisha University, Kyotanabe, Kyoto, Japan
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Natsuko Tamura
2Laboratory for Genetic Code, Graduate School of Life and Medical Sciences, Doshisha University, Kyotanabe, Kyoto, Japan
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Akira Watanabe
4Department of Life Science Frontiers, Center for iPS Cell Research and Application, Kyoto University, Kyoto, Japan
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Akira Kobayashi
1Laboratory for Genetic Code, Department of Medical Life Systems, Faculty of Life and Medical Sciences, Doshisha University, Kyotanabe, Kyoto, Japan
2Laboratory for Genetic Code, Graduate School of Life and Medical Sciences, Doshisha University, Kyotanabe, Kyoto, Japan
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  • For correspondence: akobayas@mail.doshisha.ac.jp
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Abstract

Proteasomes are protease complexes essential for cellular homeostasis, and their activity is crucial for cancer cell growth. However, the mechanism of how proteasome activity is maintained in cancer cells has remained unclear. The CNC family transcription factor NRF1 induces the expression of almost all proteasome-related genes under proteasome inhibition. NRF1 and its phylogenetically closest homolog NRF3 are both highly expressed in several types of cancers, such as colorectal cancer. Herein, we demonstrate that NRF1 and NRF3 complementarily maintain basal proteasome activity in cancer cells. A double knockdown of NRF1 and NRF3 impaired the basal proteasome activity in cancer cells and the cancer cell resistance to a proteasome inhibitor anticancer drug bortezomib by significantly reducing basal expression of seven proteasome-related genes, including PSMB3, PSMB7, PSMC2, PSMD3, PSMG2, PSMG3, and POMP. Interestingly, the molecular basis behind these cellular consequences was that NRF3 repressed NRF1 translation by the gene induction of translational regulator CPEB3, which binds to NRF1-3′UTR and decreases polysome formation on NRF1 mRNA. Consistent results were obtained from clinical analysis, wherein patients with cancer having higher CPEB3/NRF3-expressing tumors exhibit poor prognosis. These results provide the novel regulatory mechanism of basal proteasome activity in cancer cells through an NRF3-CPEB3-NRF1 translational repression axis.

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The copyright holder for this preprint is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. It is made available under a CC-BY 4.0 International license.
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Posted January 11, 2020.
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NRF1 and NRF3 complementarily maintain a basal proteasome activity in cancer cells through CPEB3-mediated translational repression
Tsuyoshi Waku, Hiroyuki Katayama, Miyako Hiraoka, Atsushi Hatanaka, Nanami Nakamura, Yuya Tanaka, Natsuko Tamura, Akira Watanabe, Akira Kobayashi
bioRxiv 2020.01.10.902718; doi: https://doi.org/10.1101/2020.01.10.902718
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NRF1 and NRF3 complementarily maintain a basal proteasome activity in cancer cells through CPEB3-mediated translational repression
Tsuyoshi Waku, Hiroyuki Katayama, Miyako Hiraoka, Atsushi Hatanaka, Nanami Nakamura, Yuya Tanaka, Natsuko Tamura, Akira Watanabe, Akira Kobayashi
bioRxiv 2020.01.10.902718; doi: https://doi.org/10.1101/2020.01.10.902718

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