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

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Abstract

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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Data availability

Supplementary information is available at Oncogene’s website. The microarray data discussed in this publication have been deposited in NCBI’s Gene Expression Omnibus [36] and are accessible through GEO Series accession number GSE125826. The mass spectrometry proteomics data discussed in this publication have been deposited to the ProteomeXchange Consortium (http://proteomecentral.proteomexchange.org) via the PRIDE partner repository (ID: PXD012858) [37].

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Acknowledgements

We would like to thank Veronica F. Blihovde, Xia Sheng and Deane Stryker for experimental help and members of the FS laboratory for helpful discussions. We would like to thank Jeffrey Petro for excellent technical support and Drs Eva Corey and Colm Morrissey of University of Washington for providing LuCaP PDX lines. This work was supported by Norwegian Research Council grant 193337, Norwegian Cancer Society grant 419204, and Health South East Norway grant 36024. The microarray gene expression service was provided by the Genomics Core Facility (GCF), Norwegian University of Science and Technology (NTNU). GCF is funded by the Faculty of Medicine at NTNU and Central Norway Regional Health Authority. The LC-MS analyses were performed by the proteomics core facility at the Department of Biosciences, University of Oslo.

Author information

NP, ML, and FS designed the study and experiments. NP and ML performed and analyzed most of the experiments. MT conducted ChIP experiments. HZN performed IP-western experiments. EA and JS performed colocalization studies. YiJ conducted nanoliposomal siRNA delivery experiments. DK contributed to growth assays. PB and AU conducted PDX-derived organoid experiments. LF and PR provided tissue microarrays of PCa, performed IHC analyses, and their interpretation. BO, NK, and HMM provided nanoliposomal siRNAs. YaJ performed IHC analyses on consecutive slides and helped with supervision. OFK did statistical analysis of IHC data. MP scored TMAs. HD provided expertize in IHC interpretation. FS supervised the project. NP, ML, and FS wrote the manuscript.

Correspondence to Fahri Saatcioglu.

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Pällmann, N., Livgård, M., Tesikova, M. et al. Regulation of the unfolded protein response through ATF4 and FAM129A in prostate cancer. Oncogene 38, 6301–6318 (2019) doi:10.1038/s41388-019-0879-2

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