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

Xia Sheng, Hatice Zeynep Nenseth, Su Qu, Omer F. Kuzu, Turid Frahnow, Lukas Simon, Stephanie Greene, Qingping Zeng, Ladan Fazli, Paul S. Rennie, Ian G. Mills, Håvard Danielsen, Fabian Theis, John B. Patterson, Yang Jin () and Fahri Saatcioglu ()
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Xia Sheng: University of Oslo
Hatice Zeynep Nenseth: University of Oslo
Su Qu: University of Oslo
Omer F. Kuzu: University of Oslo
Turid Frahnow: Helmholtz Zentrum München
Lukas Simon: Helmholtz Zentrum München
Stephanie Greene: Fosun Orinove, Inc.
Qingping Zeng: Fosun Orinove, Inc.
Ladan Fazli: The Vancouver Prostate Centre
Paul S. Rennie: The Vancouver Prostate Centre
Ian G. Mills: Queen’s University of Belfast
Håvard Danielsen: Oslo University Hospital
Fabian Theis: Helmholtz Zentrum München
John B. Patterson: Fosun Orinove, Inc.
Yang Jin: University of Oslo
Fahri Saatcioglu: University of Oslo

Nature Communications, 2019, vol. 10, issue 1, 1-12

Abstract: 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.

Date: 2019
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DOI: 10.1038/s41467-018-08152-3

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