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Oncogene. 2019 Aug;38(35):6301-6318. doi: 10.1038/s41388-019-0879-2. Epub 2019 Jul 16.

Regulation of the unfolded protein response through ATF4 and FAM129A in prostate cancer.

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Department of Biosciences, University of Oslo, Oslo, Norway.
Institute for Cancer Genetics and Informatics, Oslo University Hospital, Oslo, Norway.
Department of Cancer Immunology, Institute for Cancer Research, Oslo University Hospital, Oslo, Norway.
Department of Child and Adolescent Psychiatry, Faculty of Medicine, Dokuz Eylul University, Izmir, Turkey.
Department of Informatics, University of Oslo, Oslo, Norway.
Nuffield Division of Clinical Laboratory Sciences, University of Oxford, Oxford, UK.
Department of Experimental Therapeutics, MD Anderson Cancer Center, Houston, TX, USA.
Lombardi Comprehensive Cancer Center, Georgetown University, Washington, DC, USA.
The Vancouver Prostate Centre, Vancouver, BC, Canada.
Department of Biosciences, University of Oslo, Oslo, Norway.
Institute for Cancer Genetics and Informatics, Oslo University Hospital, Oslo, Norway.


Cancer cells exploit many of the cellular adaptive responses to support their survival needs. One such critical pathway in eukaryotic cells is the unfolded protein response (UPR) that is important in normal physiology as well as disease states, including cancer. Since UPR can serve as a lever between survival and death, regulated control of its activity is critical for tumor formation and growth although the underlying mechanisms are poorly understood. Here we show that one of the main transcriptional effectors of UPR, activating transcription factor 4 (ATF4), is essential for prostate cancer (PCa) growth and survival. Using systemic unbiased gene expression and proteomic analyses, we identified a novel direct ATF4 target gene, family with sequence similarity 129 member A (FAM129A), which is critical in mediating ATF4 effects on prostate tumorigenesis. Interestingly, FAM129A regulated both PERK and eIF2α in a feedback loop that differentially channeled the UPR output. ATF4 and FAM129A protein expression is increased in patient PCa samples compared with benign prostate. Importantly, in vivo therapeutic silencing of ATF4-FAM129A axis profoundly inhibited tumor growth in a preclinical PCa model. These data support that one of the canonical UPR branches, through ATF4 and its target gene FAM129A, is required for PCa growth and thus may serve as a novel therapeutic target.


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