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Basic Research

TCF7 is suppressed by the androgen receptor via microRNA-1-mediated downregulation and is involved in the development of resistance to androgen deprivation in prostate cancer

Prostate Cancer and Prostatic Diseases volume 20, pages 172–178 (2017)Cite this article

Subjects

Abstract

Background:

Resistance to androgen deprivation therapy (ADT) represents a key step in the malignant progression of prostate cancer, and mutation to androgen receptor (AR) is one major driver to an androgen-independent phenotype. However, alternative oncogenic pathways that bypass AR signaling have emerged as an important mechanism promoting resistance to ADT. It is known that AR activation can prevent the interaction between β-catenin and T cell factor/lymphoid enhancer-binding factor (TCF/LEF) family, inhibiting the Wnt signaling pathway. The aim of this study was to determine the role of transcription factor 7 (TCF7), a transcription factor best known as a Wnt effector that forms a complex with β-catenin, in the development of advanced prostate cancer. We further investigated the molecular mechanisms by which TCF7 is induced when AR signaling is inactivated.

Methods:

A novel AR signaling pathway that induces microRNA-1 (miR-1) to suppress metastatic prostate cancer was recently demonstrated (AR–miR-1 signaling axis), and its regulation of Wnt signaling was explored in the current study. Clinical data sets were analyzed for potential targets of AR-miR-1 signaling in the TCF/LEF family, and tissue samples were utilized to validate the relationship. The molecular mechanism and biological functions were demonstrated in prostate cancer cell lines and a mouse xenograft model.

Results:

We demonstrated a molecular mechanism of AR signaling suppressing TCF7 partly through miR-1-mediated downregulation. TCF7 exhibited oncogenic properties and compromised the tumor-suppressive effects of miR-1. Our results also showed that overexpression of TCF7 or disruption of miR-1 function promoted androgen-independent proliferation.

Conclusions:

We demonstrated that the AR–miR-1 axis negatively regulates the novel oncogenic factor, TCF7. Dysregulation of TCF7 promoted a survival advantage and resistance to androgen deprivation, suggesting its therapeutic potential for castration-resistant prostate cancer.

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References

  1. Arce L, Yokoyama NN, Waterman ML . Diversity of LEF/TCF action in development and disease. Oncogene 2006; 25: 7492–7504.

    Article  CAS  PubMed  Google Scholar 

  2. Cadigan KM, Waterman ML . TCF/LEFs and Wnt signaling in the nucleus. Cold Spring Harb Perspect Biol 2012; 4: a007906.

    Article  PubMed  PubMed Central  Google Scholar 

  3. Cui L, Guan Y, Qu Z, Zhang J, Liao B, Ma B et al. WNT signaling determines tumorigenicity and function of ESC-derived retinal progenitors. J Clin Invest 2013; 123: 1647–1661.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  4. Chen WY, Liu SY, Chang YS, Yin JJ, Yeh HL, Mouhieddine TH et al. MicroRNA-34a regulates WNT/TCF7 signaling and inhibits bone metastasis in Ras-activated prostate cancer. Oncotarget 2015; 6: 441–457.

    PubMed  Google Scholar 

  5. Hrdlickova R, Nehyba J, Bargmann W, Bose HR Jr . Multiple tumor suppressor microRNAs regulate telomerase and TCF7, an important transcriptional regulator of the Wnt pathway. PLoS ONE 2014; 9: e86990.

    Article  PubMed  PubMed Central  Google Scholar 

  6. Martens-Uzunova ES, Jalava SE, Dits NF, van Leenders GJ, Moller S, Trapman J et al. Diagnostic and prognostic signatures from the small non-coding RNA transcriptome in prostate cancer. Oncogene 2012; 31: 978–991.

    Article  CAS  PubMed  Google Scholar 

  7. Hudson RS, Yi M, Esposito D, Watkins SK, Hurwitz AA, Yfantis HG et al. MicroRNA-1 is a candidate tumor suppressor and prognostic marker in human prostatecancer. Nucleic Acids Res 2012; 40: 3689–3703.

    Article  CAS  PubMed  Google Scholar 

  8. Ambs S, Prueitt RL, Yi M, Hudson RS, Howe TM, Petrocca F et al. Genomic profiling of microRNA and messenger RNA reveals deregulated microRNA expression in prostate cancer. Cancer Res 2008; 68: 6162–6170.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  9. Liu YN, Yin JJ, Abou-Kheir W, Hynes PG, Casey OM, Fang L et al. MiR-1 and miR-200 inhibit EMT via Slug-dependent and tumorigenesis via Slug-independent mechanisms. Oncogene 2013; 32: 296–306.

    Article  CAS  PubMed  Google Scholar 

  10. Liu YN, Yin J, Barrett B, Sheppard-Tillman H, Li D, Casey OM et al. Loss of androgen-regulated microRNA 1 activates SRC and promotes prostate cancer bone metastasis. Mol Cell Biol 2015; 35: 1940–1951.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  11. Chen CD, Welsbie DS, Tran C, Baek SH, Chen R, Vessella R et al. Molecular determinants of resistance to antiandrogen therapy. Nat Med 2004; 10: 33–39.

    Article  PubMed  Google Scholar 

  12. Ford OH 3rd, Gregory CW, Kim D, Smitherman AB, Mohler JL . Androgen receptor gene amplification and protein expression in recurrent prostate cancer. The Journal of Urology 2003; 170: 1817–1821.

    Article  CAS  PubMed  Google Scholar 

  13. Scher HI, Sawyers CL . Biology of progressive, castration-resistant prostate cancer: directed therapies targeting the androgen-receptor signaling axis. J Clin Oncol 2005; 23: 8253–8261.

    Article  CAS  PubMed  Google Scholar 

  14. Niu Y, Altuwaijri S, Lai KP, Wu CT, Ricke WA, Messing EM et al. Androgen receptor is a tumor suppressor and proliferator in prostate cancer. Proc Natl Acad Sci USA 2008; 105: 12182–12187.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  15. Yuan X, Cai C, Chen S, Chen S, Yu Z, Balk SP . Androgen receptor functions in castration-resistant prostate cancer and mechanisms of resistance to new agents targeting the androgen axis. Oncogene 2014; 33: 2815–2825.

    Article  CAS  PubMed  Google Scholar 

  16. Karantanos T, Corn PG, Thompson TC . Prostate cancer progression after androgen deprivation therapy: mechanisms of castrate resistance and novel therapeutic approaches. Oncogene 2013; 32: 5501–5511.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  17. de la Taille A, Rubin MA, Chen MW, Vacherot F, de Medina SG, Burchardt M et al. Beta-catenin-related anomalies in apoptosis-resistant and hormone-refractory prostate cancer cells. Clin Cancer Res 2003; 9: 1801–1807.

    CAS  PubMed  Google Scholar 

  18. Wang G, Wang J, Sadar MD . Crosstalk between the androgen receptor and beta-catenin in castrate-resistant prostate cancer. Cancer Res 2008; 68: 9918–9927.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  19. Yu X, Wang Y, Jiang M, Bierie B, Roy-Burman P, Shen MM et al. Activation of beta-Catenin in mouse prostate causes HGPIN and continuous prostate growth after castration. Prostate 2009; 69: 249–262.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  20. Logan CY, Nusse R . The Wnt signaling pathway in development and disease. Annu Rev Cell Dev Biol 2004; 20: 781–810.

    Article  CAS  PubMed  Google Scholar 

  21. Reya T, Clevers H . Wnt signalling in stem cells and cancer. Nature 2005; 434: 843–850.

    Article  CAS  PubMed  Google Scholar 

  22. He TC, Sparks AB, Rago C, Hermeking H, Zawel L, da Costa LT et al. Identification of c-MYC as a target of the APC pathway. Science 1998; 281: 1509–1512.

    Article  CAS  PubMed  Google Scholar 

  23. Moon RT, Bowerman B, Boutros M, Perrimon N . The promise and perils of Wnt signaling through beta-catenin. Science 2002; 296: 1644–1646.

    Article  CAS  PubMed  Google Scholar 

  24. Chesire DR, Isaacs WB . Ligand-dependent inhibition of beta-catenin/TCF signaling by androgen receptor. Oncogene 2002; 21: 8453–8469.

    Article  CAS  PubMed  Google Scholar 

  25. Mulholland DJ, Read JT, Rennie PS, Cox ME, Nelson CC . Functional localization and competition between the androgen receptor and T-cell factor for nuclear beta-catenin: a means for inhibition of the Tcf signaling axis. Oncogene 2003; 22: 5602–5613.

    Article  CAS  PubMed  Google Scholar 

  26. Schweizer L, Rizzo CA, Spires TE, Platero JS, Wu Q, Lin TA et al. The androgen receptor can signal through Wnt/beta-Catenin in prostate cancer cells as an adaptation mechanism to castration levels of androgens. BMC Cell Biol 2008; 9: 4.

    Article  PubMed  PubMed Central  Google Scholar 

  27. Amir AL, Barua M, McKnight NC, Cheng S, Yuan X, Balk SP . A direct beta-catenin-independent interaction between androgen receptor and T cell factor 4. J Biol Chem 2003; 278: 30828–30834.

    Article  CAS  PubMed  Google Scholar 

  28. Taylor BS, Schultz N, Hieronymus H, Gopalan A, Xiao Y, Carver BS et al. Integrative genomic profiling of human prostate cancer. Cancer Cell 2010; 18: 11–22.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  29. Siu MK, Tsai YC, Chang YS, Yin JJ, Suau F, Chen WY et al. Transforming growth factor-beta promotes prostate bone metastasis through induction of microRNA-96 and activation of the mTOR pathway. Oncogene 2014; 34: 4767–4776.

    Article  PubMed  Google Scholar 

  30. Nelson PS, Clegg N, Arnold H, Ferguson C, Bonham M, White J et al. The program of androgen-responsive genes in neoplastic prostate epithelium. Proc Natl Acad Sci USA 2002; 99: 11890–11895.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  31. Wang G, Jones SJ, Marra MA, Sadar MD . Identification of genes targeted by the androgen and PKA signaling pathways in prostate cancer cells. Oncogene 2006; 25: 7311–7323.

    Article  CAS  PubMed  Google Scholar 

  32. Sharma NL, Massie CE, Ramos-Montoya A, Zecchini V, Scott HE, Lamb AD et al. The androgen receptor induces a distinct transcriptional program in castration-resistant prostate cancer in man. Cancer Cell 2013; 23: 35–47.

    Article  CAS  PubMed  Google Scholar 

  33. Wang Q, Li W, Zhang Y, Yuan X, Xu K, Yu J et al. Androgen receptor regulates a distinct transcription program in androgen-independent prostate cancer. Cell 2009; 138: 245–256.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  34. Hovanes K, Li TW, Munguia JE, Truong T, Milovanovic T, Lawrence Marsh J et al. Beta-catenin-sensitive isoforms of lymphoid enhancer factor-1 are selectively expressed in colon cancer. Nat Genet 2001; 28: 53–57.

    CAS  PubMed  Google Scholar 

  35. Yin J, Pollock C, Tracy K, Chock M, Martin P, Oberst M et al. Activation of the RalGEF/Ral pathway promotes prostate cancer metastasis to bone. Mol Cell Biol 2007; 27: 7538–7550.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  36. Iwamura M, Abrahamsson PA, Benning CM, Cockett AT, di Sant'Agnese PA . Androgen receptor immunostaining and its tissue distribution in formalin-fixed, paraffin-embedded sections after microwave treatment. J Histochem Cytochem 1994; 42: 783–788.

    Article  CAS  PubMed  Google Scholar 

  37. Stoyanova T, Cooper AR, Drake JM, Liu X, Armstrong AJ, Pienta KJ et al. Prostate cancer originating in basal cells progresses to adenocarcinoma propagated by luminal-like cells. Proc Natl Acad Sci USA 2013; 110: 20111–20116.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  38. Shah RB, Mehra R, Chinnaiyan AM, Shen R, Ghosh D, Zhou M et al. Androgen-independent prostate cancer is a heterogeneous group of diseases: lessons from a rapid autopsy program. Cancer Res 2004; 64: 9209–9216.

    Article  CAS  PubMed  Google Scholar 

  39. Lipianskaya J, Cohen A, Chen CJ, Hsia E, Squires J, Li Z et al. Androgen-deprivation therapy-induced aggressive prostate cancer with neuroendocrine differentiation. Asian J Androl 2014; 16: 541–544.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  40. Cai C, He HH, Chen S, Coleman I, Wang H, Fang Z et al. Androgen receptor gene expression in prostate cancer is directly suppressed by the androgen receptor through recruitment of lysine-specific demethylase 1. Cancer Cell 2011; 20: 457–471.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  41. Karatas OF, Guzel E, Suer I, Ekici ID, Caskurlu T, Creighton CJ et al. miR-1 and miR-133b are differentially expressed in patients with recurrent prostate cancer. PLoS ONE 2014; 9: e98675.

    Article  PubMed  PubMed Central  Google Scholar 

  42. Scher HI, Fizazi K, Saad F, Taplin ME, Sternberg CN, Miller K et al. Increased survival with enzalutamide in prostate cancer after chemotherapy. N Engl J Med 2012; 367: 1187–1197.

    Article  CAS  PubMed  Google Scholar 

  43. Schrader AJ, Boegemann M, Ohlmann CH, Schnoeller TJ, Krabbe LM, Hajili T et al. Enzalutamide in castration-resistant prostate cancer patients progressing after docetaxel and abiraterone. Eur Urol 2014; 65: 30–36.

    Article  CAS  PubMed  Google Scholar 

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Acknowledgements

This work was jointly supported by grants from the Ministry of Science and Technology of Taiwan to MKS (MOST 104-2320-B-038-038 and MOST 105-2628-B-038-006-MY3), MOST 104-2314-B-038-045-MY3 to Y-NL and MOST 104-2320-B-038-055-MY3 to Y-CT, from the National Health Research Institutes of Taiwan (NHRI-EX105-10308BC) to Y-NL and from Taipei Medical University-Wan Fang Hospital (104TMU-WFH-04) to Y-NL.

Author information

Author notes

  1. M K Siu and W-Y Chen: These two authors contributed equally to this work.

Authors and Affiliations

  1. PhD Program for Cancer Biology and Drug Discovery, College of Medical Science and Technology, Taipei Medical University and Academia Sinica, Taipei, Taiwan

    M K Siu, Y-C Tsai & Y-N Liu

  2. Graduate Institute of Cancer Biology and Drug Discovery, College of Medical Science and Technology, Taipei Medical University, Taipei, Taiwan

    M K Siu, H-Y Tsai, Y-C Tsai & Y-N Liu

  3. Department of Anesthesiology, Wan Fang Hospital, Taipei Medical University, Taipei, Taiwan

    M K Siu

  4. Department of Pathology, Wan Fang Hospital, Taipei Medical University, Taipei, Taiwan

    W-Y Chen

  5. Department of Pathology, School of Medicine, College of Medicine, Taipei Medical University, Taipei, Taiwan

    W-Y Chen & C-L Chen

  6. Graduate Institute of Clinical Medicine, College of Medicine, Taipei Medical University, Taipei, Taiwan

    W-Y Chen & C-L Chen

  7. Institute of Statistical Science, Academia Sinica, Taipei, Taiwan

    H-Y Chen

  8. Cell and Cancer Biology Branch, National Cancer Institute, National Institutes of Health, Bethesda, MD, USA

    J J Yin

  9. Department of Pathology, Taipei Medical University Hospital, Taipei Medical University, Taipei, Taiwan

    C-L Chen

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Correspondence to Y-N Liu.

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Siu, M., Chen, WY., Tsai, HY. et al. TCF7 is suppressed by the androgen receptor via microRNA-1-mediated downregulation and is involved in the development of resistance to androgen deprivation in prostate cancer. Prostate Cancer Prostatic Dis 20, 172–178 (2017). https://doi.org/10.1038/pcan.2017.2

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