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

Oncogene volume 38, pages 6301–6318 (2019)Cite this article

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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].

References

  1. Clarke HJ, Chambers JE, Liniker E, Marciniak SJ. Endoplasmic reticulum stress in malignancy. Cancer Cell. 2014;25:563–73.

    Article  CAS  Google Scholar 

  2. Wang M, Kaufman RJ. The impact of the endoplasmic reticulum protein-folding environment on cancer development. Nat Rev Cancer. 2014;14:581–97.

    Article  CAS  Google Scholar 

  3. Chevet E, Hetz C, Samali A. Endoplasmic reticulum stress-activated cell reprogramming in oncogenesis. Cancer Discov. 2015;5:586–97.

    Article  CAS  Google Scholar 

  4. Ameri K, Harris AL. Activating transcription factor 4. Int J Biochem Cell Biol. 2008;40:14–21.

    Article  CAS  Google Scholar 

  5. Wortel IMN, van der Meer LT, Kilberg MS, van Leeuwen FN. Surviving stress: modulation of ATF4-mediated stress responses in normal and malignant cells. Trends Endocrinol Metab. 2017;28:794–806.

    Article  CAS  Google Scholar 

  6. Han J, Back SH, Hur J, Lin YH, Gildersleeve R, Shan J, et al. ER-stress-induced transcriptional regulation increases protein synthesis leading to cell death. Nat Cell Biol. 2013;15:481–90.

    Article  CAS  Google Scholar 

  7. Attard G, Parker C, Eeles RA, Schröder F, Tomlins SA, Tannock I, et al. Prostate cancer. Lancet. 2016;387:70–82.

    Article  Google Scholar 

  8. Storm M, Sheng X, Arnoldussen YJ, Saatcioglu F. Prostate cancer and the unfolded protein response. Oncotarget. 2016;7:54051–66.

    Article  Google Scholar 

  9. Sheng X, Arnoldussen YJ, Storm M, Tesikova M, Nenseth HZ, Zhao S, et al. Divergent androgen regulation of unfolded protein response pathways drives prostate cancer. EMBO Mol Med. 2015;7:788–801.

    Article  CAS  Google Scholar 

  10. Ye J, Kumanova M, Hart LS, Sloane K, Zhang H, De Panis DN, et al. The GCN2-ATF4 pathway is critical for tumour cell survival and proliferation in response to nutrient deprivation. EMBO J. 2010;29:2082–96.

    Article  CAS  Google Scholar 

  11. Jin Y, Qu S, Tesikova M, Wang L, Kristian A, Maelandsmo GM, et al. Molecular circuit involving KLK4 integrates androgen and mTOR signaling in prostate cancer. Proc Natl Acad Sci USA. 2013;110:E2572–2581.

    Article  CAS  Google Scholar 

  12. Mills IG. Maintaining and reprogramming genomic androgen receptor activity in prostate cancer. Nat Rev Cancer. 2014;14:187–98.

    Article  CAS  Google Scholar 

  13. Shan J, Zhang F, Sharkey J, Tang TA, Ord T, Kilberg MS. The C/ebp-Atf response element (CARE) location reveals two distinct Atf4-dependent, elongation-mediated mechanisms for transcriptional induction of aminoacyl-tRNA synthetase genes in response to amino acid limitation. Nucleic Acids Res. 2016;44:9719–32.

    CAS  PubMed  PubMed Central  Google Scholar 

  14. Kilberg MS, Balasubramanian M, Fu L, Shan J. The transcription factor network associated with the amino acid response in mammalian cells. Adv Nutr. 2012;3:295–306.

    Article  CAS  Google Scholar 

  15. Yu K, Mo D, Wu M, Chen H, Chen L, Li M, et al. Activating transcription factor 4 regulates adipocyte differentiation via altering the coordinate expression of CCATT/enhancer binding protein beta and peroxisome proliferator-activated receptor gamma. FEBS J. 2014;281:2399–409.

    Article  CAS  Google Scholar 

  16. Cohen DM, Won KJ, Nguyen N, Lazar MA, Chen CS, Steger DJ. ATF4 licenses C/EBPbeta activity in human mesenchymal stem cells primed for adipogenesis. Elife. 2015;4:e06821.

    Article  Google Scholar 

  17. Sun GD, Kobayashi T, Abe M, Tada N, Adachi H, Shiota A, et al. The endoplasmic reticulum stress-inducible protein Niban regulates eIF2alpha and S6K1/4E-BP1 phosphorylation. Biochem Biophys Res Commun. 2007;360:181–7.

    Article  CAS  Google Scholar 

  18. Shaw GL, Whitaker H, Corcoran M, Dunning MJ, Luxton H, Kay J, et al. The early effects of rapid androgen deprivation on human prostate cancer. Eur Urol. 2016;70:214–8.

    Article  CAS  Google Scholar 

  19. Massie CE, Lynch A, Ramos-Montoya A, Boren J, Stark R, Fazli L, et al. The androgen receptor fuels prostate cancer by regulating central metabolism and biosynthesis. EMBO J. 2011;30:2719–33.

    Article  CAS  Google Scholar 

  20. Thomas BC, Kay JD, Menon S, Vowler SL, Dawson SN, Bucklow LJ, et al. Whole blood mRNA in prostate cancer reveals a four-gene androgen regulated panel. Endocr Relat Cancer. 2016;23:797–812.

    Article  CAS  Google Scholar 

  21. Halterman MW, De Jesus C, Rempe DA, Schor NF, Federoff HJ. Loss of c/EBP-beta activity promotes the adaptive to apoptotic switch in hypoxic cortical neurons. Mol Cell Neurosci. 2008;38:125–37.

    Article  CAS  Google Scholar 

  22. Ji H, Ding Z, Hawke D, Xing D, Jiang BH, Mills GB, et al. AKT-dependent phosphorylation of Niban regulates nucleophosmin- and MDM2-mediated p53 stability and cell apoptosis. EMBO Rep. 2012;13:554–60.

    Article  CAS  Google Scholar 

  23. Adachi H, Majima S, Kon S, Kobayashi T, Kajino K, Mitani H, et al. Niban gene is commonly expressed in the renal tumors: a new candidate marker for renal carcinogenesis. Oncogene. 2004;23:3495–3500.

    Article  CAS  Google Scholar 

  24. Ito S, Fujii H, Matsumoto T, Abe M, Ikeda K, Hino O. Frequent expression of Niban in head and neck squamous cell carcinoma and squamous dysplasia. Head Neck. 2010;32:96–103.

    PubMed  Google Scholar 

  25. Kannangai R, Diehl AM, Sicklick J, Rojkind M, Thomas D, Torbenson M. Hepatic angiomyolipoma and hepatic stellate cells share a similar gene expression profile. Hum Pathol. 2005;36:341–7.

    Article  CAS  Google Scholar 

  26. Pakos-Zebrucka K, Koryga I, Mnich K, Ljujic M, Samali A, Gorman AM. The integrated stress response. EMBO Rep. 2016;17:1374–95.

    Article  CAS  Google Scholar 

  27. Harding HP, Zhang Y, Zeng H, Novoa I, Lu PD, Calfon M, et al. An integrated stress response regulates amino acid metabolism and resistance to oxidative stress. Mol Cell. 2003;11:619–33.

    Article  CAS  Google Scholar 

  28. Yuki R, Aoyama K, Kubota S, Yamaguchi N, Kubota S, Hasegawa H, et al. Overexpression of zinc-finger protein 777 (ZNF777) inhibits proliferation at low cell density through down-regulation of FAM129A. J Cell Biochem. 2015;116:954–68.

    Article  CAS  Google Scholar 

  29. Evstafieva AG, Kovaleva IE, Shoshinova MS, Budanov AV, Chumakov PM. Implication of KRT16, FAM129A and HKDC1 genes as ATF4 regulated components of the integrated stress response. PLoS ONE. 2018;13:e0191107.

    Article  Google Scholar 

  30. Quirós PM, Prado MA, Zamboni N, D’Amico D, Williams RW, Finley D, et al. Multi-omics analysis identifies ATF4 as a key regulator of the mitochondrial stress response in mammals. J Cell Biol. 2017;216:2027–45.

    Article  Google Scholar 

  31. Marshall CJ. Specificity of receptor tyrosine kinase signaling: transient versus sustained extracellular signal-regulated kinase activation. Cell. 1995;80:179–85.

    Article  CAS  Google Scholar 

  32. Sheng X, Nenseth HZ, Qu S, Kuzu OF, Frahnow T, Simon L, et al. IRE1α-XBP1s pathway promotes prostate cancer by activating c-MYC signaling. Nat Commun. 2019;10:323.

    Article  Google Scholar 

  33. Brijwani N, Jain M, Dhandapani M, Zahed F, Mukhopadhyay P, Biswas M, et al. Rationally co-targeting divergent pathways in KRAS wild-type colorectal cancers by CANscript technology reveals tumor dependence on Notch and Erbb2. Sci Rep. 2017;7:1502.

    Article  Google Scholar 

  34. Nevedomskaya E, Baumgart SJ, Haendler B. Recent advances in prostate cancer treatment and drug discovery. Int J Mol Sci. 2018;19, 1359–84.

    Article  Google Scholar 

  35. Jin Y, Wang L, Qu S, Sheng X, Kristian A, Maelandsmo GM, et al. STAMP2 increases oxidative stress and is critical for prostate cancer. EMBO Mol Med. 2015;7:315–31.

    Article  CAS  Google Scholar 

  36. Edgar R, Domrachev M, Lash AE. Gene expression omnibus: NCBI gene expression and hybridization array data repository. Nucleic Acids Res. 2002;30:207–10.

    Article  CAS  Google Scholar 

  37. Vizcaíno JA, Côté RG, Csordas A, Dianes JA, Fabregat A, Foster JM, et al. The PRoteomics IDEntifications (PRIDE) database and associated tools: status in 2013. Nucleic Acids Res. 2013;41:D1063–1069.

    Article  Google Scholar 

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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.

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Author notes

  1. Yixin Jin

    Present address: Department of Cancer Immunology, Institute for Cancer Research, Oslo University Hospital, Oslo, Norway

  2. Dogukan Koc

    Present address: Department of Child and Adolescent Psychiatry, Faculty of Medicine, Dokuz Eylul University, Izmir, Turkey

Authors and Affiliations

  1. Department of Biosciences, University of Oslo, Oslo, Norway

    Nora Pällmann, Marte Livgård, Martina Tesikova, Hatice Zeynep Nenseth, Erman Akkus, Jørgen Sikkeland, Yixin Jin, Dogukan Koc, Omer Faruk Kuzu, Yang Jin & Fahri Saatcioglu

  2. Institute for Cancer Genetics and Informatics, Oslo University Hospital, Oslo, Norway

    Marte Livgård, Jørgen Sikkeland, Manohar Pradhan, Håvard E. Danielsen, Yang Jin & Fahri Saatcioglu

  3. Department of Informatics, University of Oslo, Oslo, Norway

    Håvard E. Danielsen

  4. Nuffield Division of Clinical Laboratory Sciences, University of Oxford, Oxford, UK

    Håvard E. Danielsen

  5. Department of Experimental Therapeutics, MD Anderson Cancer Center, Houston, TX, USA

    Nermin Kahraman, Hamada M. Mokhlis & Bulent Ozpolat

  6. Lombardi Comprehensive Cancer Center, Georgetown University, Washington, DC, USA

    Partha P. Banerjee & Aykut Uren

  7. The Vancouver Prostate Centre, Vancouver, BC, Canada

    Ladan Fazli & Paul S. Rennie

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Contributions

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.

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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). https://doi.org/10.1038/s41388-019-0879-2

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