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Nat Commun. 2019 Jan 24;10(1):323. doi: 10.1038/s41467-018-08152-3.

IRE1α-XBP1s pathway promotes prostate cancer by activating c-MYC signaling.

Author information

1
Department of Biosciences, University of Oslo, 0316, Oslo, Norway.
2
School of Public Health, Tongji Medical College, Huazhong University of Science and Technology, 430030, Wuhan, China.
3
Institute of Computational Biology, Helmholtz Zentrum München, 85764, Neuherberg, Germany.
4
Faculty of Business Administration and Economics, Chair DataScience, University Bielefeld, 33615, Bielefeld, Germany.
5
Fosun Orinove, Inc., Unit 211, Building A4, 218 Xinhu Street, 215000, SuZhou, China.
6
The Vancouver Prostate Centre, Vancouver, BC, V6H3Z6, Canada.
7
Movember/PCUK Centre of Excellence for Prostate Cancer Research, Centre for Cancer Research and Cell Biology (CCRCB), Queen's University of Belfast, Belfast, BT7 1NN, UK.
8
Institute for Cancer Genetics and Informatics, Oslo University Hospital, 0379, Oslo, Norway.
9
Center for Cancer Biomedicine, University of Oslo, 0316, Oslo, Norway.
10
Department of Informatics, University of Oslo, 0316, Oslo, Norway.
11
Nuffield Division of Clinical Laboratory Sciences, University of Oxford, Oxford, OX3 7LF, UK.
12
Department of Biosciences, University of Oslo, 0316, Oslo, Norway. yang.jin@ibv.uio.no.
13
Institute for Cancer Genetics and Informatics, Oslo University Hospital, 0379, Oslo, Norway. yang.jin@ibv.uio.no.
14
Department of Biosciences, University of Oslo, 0316, Oslo, Norway. fahris@ibv.uio.no.
15
Institute for Cancer Genetics and Informatics, Oslo University Hospital, 0379, Oslo, Norway. fahris@ibv.uio.no.

Abstract

Activation of endoplasmic reticulum (ER) stress/the unfolded protein response (UPR) has been linked to cancer, but the molecular mechanisms are poorly understood and there is a paucity of reagents to translate this for cancer therapy. Here, we report that an IRE1α RNase-specific inhibitor, MKC8866, strongly inhibits prostate cancer (PCa) tumor growth as monotherapy in multiple preclinical models in mice and shows synergistic antitumor effects with current PCa drugs. Interestingly, global transcriptomic analysis reveal that IRE1α-XBP1s pathway activity is required for c-MYC signaling, one of the most highly activated oncogenic pathways in PCa. XBP1s is necessary for optimal c-MYC mRNA and protein expression, establishing, for the first time, a direct link between UPR and oncogene activation. In addition, an XBP1-specific gene expression signature is strongly associated with PCa prognosis. Our data establish IRE1α-XBP1s signaling as a central pathway in PCa and indicate that its targeting may offer novel treatment strategies.

PMID:
30679434
PMCID:
PMC6345973
DOI:
10.1038/s41467-018-08152-3
[Indexed for MEDLINE]
Free PMC Article

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