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Loss of ATF3 promotes Akt activation and prostate cancer development in a Pten knockout mouse model

Oncogene volume 34, pages 4975–4984 (2015)Cite this article

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Abstract

Activating transcription factor 3 (ATF3) responds to diverse cellular stresses, and regulates oncogenic activities (for example, proliferation, survival and migration) through direct transcriptional regulation or protein-protein interactions. Although aberrant ATF3 expression is frequently found in human cancers, the role of ATF3 in tumorigenesis is poorly understood. Here, we demonstrate that ATF3 suppresses the development of prostate cancer induced by knockout of the tumor suppressor Pten in mouse prostates. Whereas the oncogenic stress elicited by Pten loss induced ATF3 expression in prostate epithelium, we found that ATF3 deficiency increased cell proliferation and promoted cell survival, leading to early onset of mouse prostatic intraepithelial neoplasia and the progression of prostate lesions to invasive adenocarcinoma. Importantly, the loss of ATF3 promoted activation of the oncogenic AKT signaling evidenced by high levels of phosphorylated AKT and S6 proteins in ATF3-null prostate lesions. In line with these in vivo results, knockdown of ATF3 expression in human prostate cancer cells by single guided RNA-mediated targeting activated AKT and increased matrix metalloproteinase-9 expression. Our results thus link ATF3 to the AKT signaling, and suggest that ATF3 is a tumor suppressor for the major subset of prostate cancers harboring dysfunctional Pten.

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References

  1. Shen MM, Abate-Shen C . Molecular genetics of prostate cancer: New prospectes for old challenges. Gene Dev 2010; 24: 1967–2000.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  2. Song MS, Salmena L, Pandolfi PP . The functions and regulation of the PTEN tumour suppressor. Nat Rev Mol Cell Biol 2013; 13: 283–296.

    Article  Google Scholar 

  3. Wang S, Gao J, Lei Q, Rozengurt N, Pritchard C, Jiao J et al. Prostate-specific deletion of the muring Pten tumor suppressor gene leads to metastatic prostate cancer. Cancer Cell 2003; 4: 209–221.

    Article  CAS  PubMed  Google Scholar 

  4. Mulholland DJ, Tran LM, Li Y, Cai H, Morim A, Wang S et al. Cell autonomous role of PTEN in regulating castration-resistant prostate cancer growth. Cancer Cell 2011; 19: 792–804.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  5. Carverm BS, Chapinski C, Wongvipat J, Hieronymus H, Chen Y, Chandarlapaty S et al. Reciprocal feedback regulation of PI3K and androgen receptor signaling in PTEN-deficient prostate cancer. Cancer Cell 2011; 19: 575–586.

    Article  Google Scholar 

  6. Hai T, Wolfgang CD, Marsee DK, Allen AE, Sivaprasad U . ATF3 and stress responses. Gene Expr 1999; 7: 321–325.

    CAS  PubMed  Google Scholar 

  7. Yan C, Lu D, Hai T, Boyd DD . Activating transcription factor 3, a stress sensor, activates p53 by blocking its ubiquitination. EMBO J 2005; 24: 2425–2435.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  8. Gilchrist M, Thorsson V, Li B, Rust AG, Korb M, Roach JC et al. Systems biology approaches identify ATF3 as a negative regulator of Toll-like receptor 4. Nature 2006; 441: 173–178.

    Article  CAS  PubMed  Google Scholar 

  9. Kang Y, Chen C, Massague J . A self-enabling TGFß response coupled to stress signaling: Smad engages stress response factor ATF3 for Id1 repression in epithelial Cells. Mol Cell 2003; 11: 915–926.

    Article  CAS  PubMed  Google Scholar 

  10. Hoetzenecker W, Echtenacher B, Guenova E, Hoetzenecker K, Woelbing F, Bruck J et al. ROS-induced ATF3 causes susceptibility to secondary infections during sepsis-associated immunosuppression. Nat Med 2011; 18: 128–134.

    Article  PubMed  PubMed Central  Google Scholar 

  11. Wu X, Nguyen B, Dziunycz P, Chang S, Brooks Y, Lefort K et al. Opposing roles for calcineurin and ATF3 in squamous skin cancer. Nature 2010; 465: 368–372.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  12. Hai T, Wolford CC, Chang Y-S . ATF3, a hub of the cellular adaptive-response network, in the pathogenesis of diseases: Is modulation of inflammation a unifying component? Gene Exp 2010; 15: 1–11.

    Article  CAS  Google Scholar 

  13. Huang X, Li X, Guo B . KLF6 induced apoptosis in prostate cancer cells through upregulation of ATF3. J Biol Chem 2008; 283: 29795–29801.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  14. Liu Y, Gao F, Jiang H, Niu L, Bi Y, Young CY et al. Induction of DNA damage and ATF3 by retigeric acid B, a novel topoisomeriase II inhibitor, promotes apoptosis in prostate cancer cells. Cancer Lett 2013; 337: 66–76.

    Article  CAS  PubMed  Google Scholar 

  15. Lapointe J, Li C, Higgins JP, Van De Rijn M, Bair E, Montgomery K et al. Gene expression profiling identifies clinically relevant subtypes of prostate cancer. Proc Natl Acad Sci USA 2004; 101: 811–816.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  16. Tomlins SA, Mehra R, Rhodes DR, Cao X, Wang L, Dhanasekaran SM et al. Integrative molecular concept modeling of prostate cancer progression. Nat Genet 2011; 39: 41–51.

    Article  Google Scholar 

  17. Gargiulo G, Cesaroni M, Serresi M, de Vries N, Hulsman D, Bruggeman SW et al. In vivo RNAi screen for BMI1 targets identifies TGF-β/BMP-ER stress pathways as key regulators of neural- and malignant glioma-stem cell homeostasis. Cancer Cell 2013; 23: 660–676.

    Article  CAS  PubMed  Google Scholar 

  18. Hackl C, Lang SA, Moser C, Mori A, Fichtner-Feigl S, Hellerbrand C et al. Activating transcription factor-3 (ATF3) functions as a tumor suppressor in colon cancer and is up-regulated upon heat-shock protein 90 (Hsp90) inhibition. BMC Cancer 2010; 10: 668.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  19. Yuan X, Yu L, Li J, Xie G, Rong T, Zhang L et al. ATF3 suppresses metastasis of bladder cancer by regulating gelsolin-mediated remodeling of the actin cytoskeleton. Cancer Res 2013; 73: 3625–3637.

    Article  CAS  PubMed  Google Scholar 

  20. Jan Y-H, Tsai H-Y, Yang C-J, Huang M-S, Yang Y-F, Lai T-C et al. Adenylate kinase-4 is a marker of poor clinical outcomes that promotes metastasis of lung cancer by downregulating the transcription factor 3. Cancer Res 2012; 72: 5119–5129.

    Article  CAS  PubMed  Google Scholar 

  21. Ishiguro T, Nakajima M, Naito M, Muto T, Tsuruo T . Identification of genes differentially expressed in B16 murine melanoma sublines with different metastatic potentials. Cancer Res 1996; 56: 875–879.

    CAS  PubMed  Google Scholar 

  22. Bandyopadhyay S, Wang Y ZR, Pai S, Watabe M, Iiizumi M, Furuta E et al. The tumor metastasis suppressor gene Drg-1 down-regulates the expression of activating transcription factor 3 in prostate cancer. Cancer Res 2006; 66: 11983–11990.

    Article  CAS  PubMed  Google Scholar 

  23. Wolford CC, McConoughey SJ, Jalgaonkar SP, Leon M, Merchant AS, Dominick JL et al. Transcription factor ATF3 links host adaptive response to breast cancer metastasis. J Clin Invest 2013; 123: 2893–2906.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  24. Wang H, Jiang M, Cui H, Chen M, Buttyan R, Hayward SW et al. The stress response mediator ATF3 represses androgen signaling by binding the androgen receptor. Mol Cell Biol 2012; 32: 3190–3202.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  25. Chen Z, Trotman LC, Shaffer D, Lin H-H, Dotan ZA, Niki M et al. Crucial role of p53-dependent cellular senescence in suppression of Pten-deficient tumorigenesis. Nature 2005; 436: 725–730.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  26. Svensson RU, Haverkamp JM, Thedens DR, Cohen MB, Ratliff TL, Henry MD . Slow disease progression in a C57BL/6 Pten-deficient mouse model of prostate cancer. Am J Pathol 2012; 179: 502–512.

    Article  Google Scholar 

  27. Blando J, Portis M, Benavides F, Alexander A, Mills G, Dave B et al. PTEN deficiency is fully penetrant for prostate adenocarcinoma in C57BL/6 mice via mTOR-dependent growth. Am J Pathol 2009; 174: 1869–1879.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  28. Mali P, Yang L, Esvelt KM, Aach J, Guell M, DiCarlo JE et al. RNA-guided human genome engineering via Cas9. Science 2013; 339: 823–826.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  29. Romashkova J, Makarov SS . NF-κB is a target of AKT in anti-apoptotic PDGF signalling. Nature 1999; 401: 86–90.

    Article  CAS  PubMed  Google Scholar 

  30. Madrid LV, Mayo MW, Reuther JY, Baldwin AS . Akt stimulates the transactivation potential of the RelA/p65 subunit of NF-κB through utilization of the IκB kinase and activation of the mitogen-activated protein kinase p38. J Biol Chem 2001; 276: 18934–18940.

    Article  CAS  PubMed  Google Scholar 

  31. Yan C, Wang H, Boyd DD . KiSS-1 represses 92-kDa type IV collagenase expression by down-regulating NF-κB binding to the promoter as a consequence of IκBα-induced block of p65/p50 nuclear translocation. J Biol Chem 2001; 276: 1164–1172.

    Article  CAS  PubMed  Google Scholar 

  32. Yan C, Boyd DD . Regulation of matrix metalloproteinase gene expression. J Cell Physiol 2007; 211: 19–26.

    Article  CAS  PubMed  Google Scholar 

  33. Agarwal A, Das K, Lerner N, Sathe S, Cicek M, Casey G et al. The AKT/IκB kinase pathway promotes angiogenic/metastatic gene expression in colorectal cancer by activating nuclear factor-κB and β-catenin. Oncogene 2005; 24: 1021–1031.

    Article  CAS  PubMed  Google Scholar 

  34. Yan C, Wang H, Boyd DD . ATF3 represses 72-kDa type IV collagenase (MMP-2) expression by antagonizing p53-dependent trans-activation of the collagenase promoter. J Biol Chem 2002; 277: 10804–10812.

    Article  CAS  PubMed  Google Scholar 

  35. Chen HH, Wang DL . Nitric oxide inhibits matrix metalloproteinase-2 expression via the induction of activating transcription factor 3 in endothelial cells. Mol Pharmacol 2004; 65: 1130–1140.

    Article  CAS  PubMed  Google Scholar 

  36. Stearns ME, Kim G, Garcia F, Wang M . Interleukin-10 induced activating transcription factor 3 transcriptional suppression of matrix metalloproteinase-2 gene expression in human prostate CPTX-1532 cells. Mol Cancer Res 2004; 2: 403–416.

    CAS  PubMed  Google Scholar 

  37. Lu D, Wolfgang C, Hai T . Activating transcription factor 3, a stress-inducible gene, suppresses Ras-stimulated tumorigenesis. J Biol Chem 2006; 281: 10473–10481.

    Article  CAS  PubMed  Google Scholar 

  38. Liu W, Liizumi-Gairani M, Okuda H, Kobayashi A, Watabe M, Pai SK et al. KAI1 gene is engaged in NDRG1 gene-mediated metastasis suppression through the ATF3-NFκB complex in human prostate cancer. J Biol Chem 2011; 286: 18949–18959.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  39. Wei S, Wang H, Lu C, Malmut S, Zhang J, Ren S et al. The activating transcription factor 3 protein suppresses the oncogenic function of mutant p53 proteins. J Biol Chem 2014; 289: 8947–8959.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  40. Varambally S, Yu J, Laxman B, Rhodes DR, Mehra R, Tomlins SA et al. Integrative genomic and proteomic analysis of prostate cancer reveals signatures of metastatic progression. Cancer Cell 2012; 8: 393–406.

    Article  Google Scholar 

  41. Yu YP, Landsittel D, Jing L, Nelson J, Ren B, Liu L et al. Gene expression alterations in prostate cancer predicting tumor aggression and preceding development of malignancy. J Clin Oncol 2004; 22: 2790–2799.

    Article  CAS  PubMed  Google Scholar 

  42. Chen BPC, Liang G, Whelan J, Hai T . ATF3 and ATF3ΔZip: Transcriptional repression versus activation by alternatively spliced isoforms. J Biol Chem 1994; 269: 15819–15826.

    CAS  PubMed  Google Scholar 

  43. Nakagomi S, Suzuki Y, Namikawa K, Kiryu-Seo S, Kiyama H . Expression of the activating transcription factor 3 prevents c-Jun N-terminal kinase-induced neuronal death by promoting heat shock protein 27 expression and Akt activation. J Neurosci 2003; 23: 5187–5196.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  44. Gilchrist M, Henderson WR Jr, Morotti A, Johnson CD, Nachman A, Schmitz F et al. A key role for ATF3 in regulating mast cell survival and mediator release. Blood 2010; 115: 4734–4741.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  45. Liu YP, Liao WC, Ger LP, Chen JC, Hsu TI, Lee YC et al. Carboxyl-terminal modulator protein positively regulates Akt phosphorylation and acts as an oncogenic driver in breast cancer. Cancer Res 2013; 73: 6194–6205.

    Article  CAS  PubMed  Google Scholar 

  46. Huang CY, Chen JJ, Wu JS, Tsai HD, Lin H, Yan YT et al. Novel link of anti-apoptotic ATF3 with pro-apoptotic CTMP in the ischemic brain. Mol Neurobiol (e-pub ahead of print 26 April 2014; doi:10.1007/s12035-014-8710-0.

    Article  PubMed  Google Scholar 

  47. Manning BD, Cantley LC . AKT/PKB signaling: Navigating downstream. Cell 2007; 129: 1261–1274.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  48. Freeman D, Lesche R, Kertesz N, Wang S, Li G, Gao J et al. Genetic background controls tumor development in Pten-deficient mice. Cancer Res 2006; 66: 6492–6496.

    Article  CAS  PubMed  Google Scholar 

  49. Zhang Q, Liu S, Ge D, Zhang Q, Xue Y, Xiong Z et al. Interleukin-17 promotes formation and growth of prostate adenocarcinoma in mouse models. Cancer Res 2012; 72: 2589–2599.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  50. Hartman MG, Lu D, Kim ML, Kociba GJ, Shukri T, Buteau J et al. Role for activating transcription factor 3 in stress-induced β-cell apoptosis. Mol Cell Biol 2004; 24: 5721–5732.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  51. Yan C, Boyd DD . Histone H3 acetylation and H3 K4 methylation define distinct chromatin regions permissive for transgene expression. Mol Cell Biol 2006; 26: 6357–6371.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

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Acknowledgements

This work was supported by NIH grants R01CA139107, R01CA164006 and a Department of Defense award W81XWH-07-1-0095 to CY. We thank Dr George Church for providing sgRNA targeting reagents and Dr Honglin Li for providing NF-κB reagents.

Author Contributions

ZY and DX bred the mice. ZY carried out the experiments with the help of HD and JZ, JK performed statistical analyses of clinical data. TH provided the ATF3−/− mice and analyzed the data. HD, JZ and TH edited the manuscript. CY conceived the study, analyzed the data and wrote the manuscript.

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Authors and Affiliations

  1. GRU Cancer Center, Georgia Regents University, Augusta, GA, USA

    Z Wang, H-F Ding & C Yan

  2. Center for Cell Biology and Cancer Research, Albany Medical College, Albany, NY, USA

    Z Wang, D Xu & C Yan

  3. Department of Pathology, Georgia Regents University, Augusta, GA, USA

    H-F Ding

  4. Department of Biostatistics & Epidemiology, Georgia Regents University, Augusta, GA, USA

    J Kim

  5. Department of Radiation Oncology, School of Medicine, Case Western Reserve University, Cleveland, OH, USA

    J Zhang

  6. Department of Molecular and Cellular Biochemistry, Ohio State University, Columbus, OH, USA

    T Hai

  7. Department of Biochemistry and Molecular Biology,

    C Yan

  8. Georgia Regents University, Augusta, GA, USA

    C Yan

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Correspondence to C Yan.

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Wang, Z., Xu, D., Ding, HF. et al. Loss of ATF3 promotes Akt activation and prostate cancer development in a Pten knockout mouse model. Oncogene 34, 4975–4984 (2015). https://doi.org/10.1038/onc.2014.426

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