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Loss of ATF3 promotes hormone-induced prostate carcinogenesis and the emergence of CK5+CK8+ epithelial cells

Oncogene volume 35, pages 3555–3564 (2016)Cite this article

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Abstract

Steroid sex hormones can induce prostate carcinogenesis, and are thought to contribute to the development of prostate cancer during aging. However, the mechanism for hormone-induced prostate carcinogenesis remains elusive. Here, we report that activating transcription factor 3 (ATF3)—a broad stress sensor—suppressed hormone-induced prostate carcinogenesis in mice. Although implantation of testosterone and estradiol (T+E2) pellets for 2 months in wild-type mice rarely induced prostatic intraepithelial neoplasia (PIN) in dorsal prostates (one out of eight mice), the loss of ATF3 led to the appearance of not only PIN but also invasive lesions in almost all examined animals. The enhanced carcinogenic effects of hormones on ATF3-deficient prostates did not appear to be caused by a change in estrogen signaling, but were more likely a consequence of elevated androgen signaling that stimulated differentiation of prostatic basal cells into transformation-preferable luminal cells. Indeed, we found that hormone-induced lesions in ATF3-knockout mice often contained cells with both basal and luminal characteristics, such as p63+ cells (a basal-cell marker) showing luminal-like morphology, or cells double-stained with basal (CK5+) and luminal (CK8+) markers. Consistent with these findings, low ATF3 expression was found to be a poor prognostic marker for prostate cancer in a cohort of 245 patients. Our results thus support that ATF3 is a tumor suppressor in prostate cancer.

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References

  1. Ricke WA, Wang Y, Cunha GR . Steroid hormones and carcinogenesis of the prostate: The role of estrogens. Differentiation 2007; 75: 871–882.

    Article  CAS  Google Scholar 

  2. Prins GS, Korach KS . The role of estrogens and estrogen receptors in normal prostate growth and disease. Steroids 2008; 73: 233–244.

    Article  CAS  Google Scholar 

  3. Bosland MC . The role of estrogens in prostate carcinogenesis: A rationale for chemoprevention. Rev Urol 2005; 7: S4–S10.

    PubMed  PubMed Central  Google Scholar 

  4. Noble RL . The development of prostatic adenocarcinoma in Nb rats following prolonged sex hormone adminstration. Cancer Res 1977; 37: 1929–1933.

    CAS  PubMed  Google Scholar 

  5. Ricke WA, McPherson SJ, Bianco JJ, Cunha GR, Wang Y, Risbridger GP . Prostatic hormonal carcinogenesis is mediated by in situ estrogen production and estrogen receptor alpha signaling. FASEB J 2008; 22: 1512–1520.

    Article  CAS  Google Scholar 

  6. Risbridger GP, Wang H, Frydenberg M, Cunha G . The metaplastic effects of estrogen on mouse prostate epithelium: Proliferation of cells with basal cell phenotype. Endocrinol 2001; 142: 2443–2450.

    Article  CAS  Google Scholar 

  7. Risbridger G, Wang H, Young P, Kurita T, Wong YZ, Lubahn D et al. Evidence that epithelial and mesenchymal estrogen receptor-α mediates effects of estrogen on prostatic epithelim. Dev Biol 2001; 229: 432–442.

    Article  CAS  Google Scholar 

  8. Culing Z, Klocker H, Bartsch G, Steiner H, Hobisch A . Androgen receptors in prostate cancer. J Urol 2003; 170: 1363–1369.

    Article  Google Scholar 

  9. Gnanapragasam VJ, Robson CN, Leung HY, Neal DE . Androgen receptor signalling in prostate. BJU International 2000; 86: 1001–1013.

    Article  CAS  Google Scholar 

  10. Bennett NC, Gardiner RA, Hooper JD, Johnson DW, Gobe GC . Molecular cell biology of androgen receptor signaling. Int J Biochem Cell Biol 2010; 42: 813–827.

    Article  CAS  Google Scholar 

  11. Heemers HW, Tindall DJ . Androgen receptor (AR) coregulators: A diversity of functions converging on and regulating the AR transcriptional complex. Endocr Rev 2005; 28: 778–808.

    Article  Google Scholar 

  12. Wang L, Hsu C-L, Chang C . Androgen receptor corepressors: An overview. Prostate 2005; 63: 117–130.

    Article  CAS  Google Scholar 

  13. 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  Google Scholar 

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

    CAS  PubMed  Google Scholar 

  15. 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  Google Scholar 

  16. 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  Google Scholar 

  17. 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  Google Scholar 

  18. 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 Expr 2010; 15: 1–11.

    Article  CAS  Google Scholar 

  19. Thompson MR, Xu D, Williams BR . ATF3 transcription factor and its emerging role in immunity and cancer. J Mol Med 2009; 87: 1053–1060.

    Article  CAS  Google Scholar 

  20. Yan C, Boyd DD . ATF3 regulates the stability of p53: A link to cancer. Cell Cycle 2006; 5: 926–929.

    Article  CAS  Google Scholar 

  21. Wang Z, Xu D, Ding H-F, Kim J, Zhang J, Hai T, Yan C . Loss of ATF3 promotes Akt activation and prostate cancer development in a Pten knockout mouse model. Oncogene 2015; 34: 4975–4981.

    Article  CAS  Google Scholar 

  22. Wang Z, Yan C . Emerging roles of ATF3 in the suppression of prostate cancer. Mol Cell Oncol in press.

  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  Google Scholar 

  24. Wang ZA, Toivanen R, Bergren SK, Chambon P, Shen MM . Luminal cells are favored as the cell of origin for prostate cancer. Cell Rep 2014; 8: 1339–1346.

    Article  CAS  Google Scholar 

  25. 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  Google Scholar 

  26. Tomlins SA, Mehra R, Rhodes DR, Cao X, Wang L, Dhanasekaran SM et al. Integrative molecular concept modeling of prostate cancer progression. Nat Genet 2007; 39: 41–51.

    Article  CAS  Google Scholar 

  27. Lau K-M, LaSpina M, Long J, Ho S-M . Expression of estrogen receptor (ER)-α and ER-β in normal and malignant prostatic epithelial cells: Regulation by methylation and invovlvement in growth regulation. Cancer Res 2000; 60: 3175–3182.

    CAS  Google Scholar 

  28. Goldstein AS, Witte ON . Does the microenvironment influence the cell types of origin for prostate cancer? Genes Dev 2013; 27: 1539–1544.

    Article  CAS  Google Scholar 

  29. Choi N, Zhang B, Zhang L, Ittmann M, Xin L . Adult murine prostate basal and luminal cells are self-sustained lineages that can both serve as targets for prostate cancer initiation. Cancer Cell 2012; 21: 253–265.

    Article  CAS  Google Scholar 

  30. Kwon O-J, Zhang L, Ittmann MM, Xin L . Prostatic inflammation enhances basal-to-luminal differentiation and accelerates initiation of prostate cancer with a basal cell origin. Proc Natl Acad Sci USA 2014; 111: E592–E600.

    Article  CAS  Google Scholar 

  31. Bonkhoff H, Remberger K . Differantiation pathways and histogenetic aspects of normal and abnormal prostatic growth: A stem cell model. Prostate 1996; 28: 98–106.

    Article  CAS  Google Scholar 

  32. Berger R, Febbo PG, Majumder PK, Zhao JJ, Mukherjee S, Signoretti S et al. Androgen-induced differentiation and tumorigenicity of human prostate epithelial cells. Cancer Res 2004; 64: 8867–8875.

    Article  CAS  Google Scholar 

  33. Okamoto A, Iwamoto Y, Maru Y . Oxidative stress-responsive transcription factor ATF3 potentially mediates diabetic angiopathy. Mol Cell Biol 2006; 26: 1087–1097.

    Article  CAS  Google Scholar 

  34. 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  Google Scholar 

  35. 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  Google Scholar 

  36. 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  Google Scholar 

  37. Wang J, Zhu HH, Chu M, Liu Y, Zhang C, Liu G et al. Symmetrical and asymmertical division analysis provides evidence for a hierarchy of prostate epithelial cell lineages. Nat Commun 2014; 5: 4758.

    Article  CAS  Google Scholar 

  38. Lu T-L, Huang Y-F, You L-R, Chao N-C, Su F-Y, Chang J-L et al. Conditionally ablated Pten in prostate basal cells promotes basal-to-luminal differentiation and causes invasive prostate cancer in mice. Am J Pathol 2013; 182: 975–991.

    Article  CAS  Google Scholar 

  39. Ding Z, Wu CJ, Chu GC, Xiao Y, Ho D, Zhang J et al. SMAD4-depdenent barrier constrains prostate cancer growth and metastatic progression. Nature 2011; 470: 269–273.

    Article  CAS  Google Scholar 

  40. 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  Google Scholar 

  41. 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 

  42. 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  Google Scholar 

  43. Ran FA, Hsu PD, Wright J, Agarwala V, Scott DA, Zhang F . Genome engineering using the CRISPR-Cas9 system. Nat Protoc 2013; 8: 2281–2308.

    Article  CAS  Google Scholar 

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Acknowledgements

This work was supported by NIH grants R01CA139107 and R01CA164006, and a Department of Defense award W81XWH-15-1-0049 to CY. We thank Dr Ahmed Chadli for providing the PR antibody.

Author contributions

ZY bred the mice and carried out the experiments with the help of YT, HD, JZ and JKC. JK performed statistical analyses of the TCGA data. TH provided the ATF3−/− mice and analyzed the data. HD, JZ, TH and JKC 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, Y Teng, H-F Ding, J K Cowell & C Yan

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

    Z Wang & C Yan

  3. Department of Statistics, Sungkyunkwan University, Seoul, South Korea

    J Kim

  4. Department of Pathology, Medical College of Georgia, Georgia Regents University, Augusta, GA, USA

    H-F Ding

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

    J Zhang

  6. Department of Biological Chemistry and Pharmacology, Ohio State University, Columbus, OH, USA

    T Hai

  7. Department of Biochemistry and Molecular Biology, Medical College of Georgia, Georgia Regents University, Augusta, GA, USA

    C Yan

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  1. Z Wang
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Correspondence to C Yan.

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Wang, Z., Kim, J., Teng, Y. et al. Loss of ATF3 promotes hormone-induced prostate carcinogenesis and the emergence of CK5+CK8+ epithelial cells. Oncogene 35, 3555–3564 (2016). https://doi.org/10.1038/onc.2015.417

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  • DOI: https://doi.org/10.1038/onc.2015.417

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