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Androgen receptor with short polyglutamine tract preferably enhances Wnt/β-catenin-mediated prostatic tumorigenesis

Abstract

Polyglutamine (polyQ) tract polymorphism within the human androgen receptor (AR) shows population heterogeneity. African American men possess short polyQ tracts significantly more frequently than Caucasian American men. The length of polyQ tracts is inversely correlated with the risk of prostate cancer, age of onset, and aggressiveness at diagnosis. Aberrant activation of Wnt signaling also reveals frequently in advanced prostate cancer, and an enrichment of androgen and Wnt signaling activation has been observed in African American patients. Here, we assessed aberrant expression of AR bearing different polyQ tracts and stabilized β-catenin in prostate tumorigenesis using newly generated mouse models. We observed an early onset oncogenic transformation, accelerated tumor cell growth, and aggressive tumor phenotypes in the compound mice bearing short polyQ tract AR and stabilized β-catenin. RNA sequencing analysis showed a robust enrichment of Myc-regulated downstream genes in tumor samples bearing short polyQ AR versus those with longer polyQ tract AR. Upstream regulator analysis further identified Myc as the top candidate of transcriptional regulators in tumor cells from the above mouse samples with short polyQ tract AR and β-catenin. Chromatin immunoprecipitation analyses revealed increased recruitment of β-catenin and AR on the c-Myc gene regulatory locus in the tumor tissues expressing stabilized β-catenin and shorter polyQ tract AR. These data demonstrate a promotional role of aberrant activation of Wnt/β-catenin in combination with short polyQ AR expression in prostate tumorigenesis and suggest a potential mechanism underlying aggressive prostatic tumor development, which has been frequently observed in African American patients.

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Fig. 1: Generation of mouse models with stabilized β-catenin in the prostates of mice with humanized AR alleles bearing different length of CAG repeats.
Fig. 2: Humanized AR bearing shorter polyQ tracts enhances β-catenin-mediated oncogenic transformation and prostatic tumor development.
Fig. 3: Humanized AR bearing shorter polyQ tracts enhances prostatic organoid formation and accelerates tumor development and progression.
Fig. 4: The promotional role of short polyQ containing AR in inducing PIN and prostatic tumor growth and progression is androgen dependent.
Fig. 5: Humanized AR bearing shorter polyQ tracts enhances β-catenin-mediated oncogenic transformation in CK8 expressing prostatic cells.
Fig. 6: Determining the signaling pathways in mouse prostate tissues using RNAseq analysis.
Fig. 7: Investigating the molecular mechanisms for prostate tumors mediated by stabilization of β-catenin and AR bearing shorter length of PolyQ tracts.

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References

  1. Siegel RL, Miller KD, Jemal A. Cancer statistics, 2019. CA Cancer J Clin. 2019;69:7–34.

    Article  PubMed  Google Scholar 

  2. DeSantis CE, Miller KD, Goding Sauer A, Jemal A, Siegel RL. Cancer statistics for African Americans, 2019. CA Cancer J Clin. 2019;69:211–33.

    PubMed  Google Scholar 

  3. Culig Z. Role of the androgen receptor axis in prostate cancer. Urology. 2003;62:21–6.

    PubMed  Google Scholar 

  4. Kyprianou N, Isaacs JT. Activation of programmed cell death in the rat ventral prostate after castration. Endocrinology. 1988;122:552–62.

    CAS  PubMed  Google Scholar 

  5. Jenster G, van der Korput HA, van Vroonhoven C, van der Kwast TH, Trapman J, Brinkmann AO. Domains of the human androgen receptor involved in steroid binding, transcriptional activation, and subcellular localization. Mol Endocrinol. 1991;5:1396–404.

    CAS  PubMed  Google Scholar 

  6. Zhou ZX, Wong CI, Sar M, Wilson EM. The androgen receptor: an overview. Recent Prog Horm Res. 1994;49:249–74.

    CAS  PubMed  Google Scholar 

  7. Clark PE, Irvine RA, Coetzee GA. The androgen receptor CAG repeat and prostate cancer risk. Methods Mol Med. 2003;81:255–66.

    CAS  PubMed  Google Scholar 

  8. Stanford JL, Just JJ, Gibbs M, Wicklund KG, Neal CL, Blumenstein BA, et al. Polymorphic repeats in the androgen receptor gene: molecular markers of prostate cancer risk. Cancer Res. 1997;57:1194–8.

    CAS  PubMed  Google Scholar 

  9. Choong CS, Wilson EM. Trinucleotide repeats in the human androgen receptor: a molecular basis for disease. J Mol Endocrinol. 1998;21:235–57.

    CAS  PubMed  Google Scholar 

  10. Mhatre AN, Trifiro MA, Kaufman M, Kazemi-Esfarjani P, Figlewicz D, Rouleau G, et al. Reduced transcriptional regulatory competence of the androgen receptor in X-linked spinal and bulbar muscular atrophy. Nat Genet. 1993;5:184–8.

    CAS  PubMed  Google Scholar 

  11. Bennett CL, Price DK, Kim S, Liu D, Jovanovic BD, Nathan D, et al. Racial variation in CAG repeat lengths within the androgen receptor gene among prostate cancer patients of lower socioeconomic status. J Clin Oncol. 2002;20:3599–604.

    CAS  PubMed  Google Scholar 

  12. Sartor O, Zheng Q, Eastham JA. Androgen receptor gene CAG repeat length varies in a race-specific fashion in men without prostate cancer. Urology. 1999;53:378–80.

    CAS  PubMed  Google Scholar 

  13. Verras M, Sun Z. Roles and regulation of Wnt signaling and beta-catenin in prostate cancer. Cancer Lett. 2006;237:22–32.

    CAS  PubMed  Google Scholar 

  14. Robinson D, Van Allen EM, Wu Y-M, Schultz N, Lonigro RJ, Mosquera J-M, et al. Integrative clinical genomics of advanced prostate cancer. Cell. 2015;161:1215–28.

    CAS  PubMed  PubMed Central  Google Scholar 

  15. Chesire DR, Isaacs WB. Ligand-dependent inhibition of beta-catenin/TCF signaling by androgen receptor. Oncogene. 2002;21:8453–69.

    CAS  PubMed  Google Scholar 

  16. Bierie B, Nozawa M, Renou JP, Shillingford JM, Morgan F, Oka T, et al. Activation of beta-catenin in prostate epithelium induces hyperplasias and squamous transdifferentiation. Oncogene. 2003;22:3875–87.

    CAS  PubMed  Google Scholar 

  17. Gounari F, Signoretti S, Bronson R, Klein L, Sellers WR, Kum J, et al. Stabilization of beta-catenin induces lesions reminiscent of prostatic intraepithelial neoplasia, but terminal squamous transdifferentiation of other secretory epithelia. Oncogene. 2002;21:4099–107.

    CAS  PubMed  Google Scholar 

  18. Mulholland DJ, Cheng H, Reid K, Rennie PS, Nelson CC. The androgen receptor can promote beta-catenin nuclear translocation independently of adenomatous polyposis coli. J Biol Chem. 2002;277:17933–43.

    CAS  PubMed  Google Scholar 

  19. Truica CI, Byers S, Gelmann EP. Beta-catenin affects androgen receptor transcriptional activity and ligand specificity. Cancer Res. 2000;60:4709–13.

    CAS  PubMed  Google Scholar 

  20. Yang F, Li X, Sharma M, Sasaki CY, Longo DL, Lim B, et al. Linking beta-catenin to androgen-signaling pathway. J Biol Chem. 2002;277:11336–44.

    CAS  PubMed  Google Scholar 

  21. Lee SH, Luong R, Johnson DT, Cunha GR, Rivina L, Gonzalgo ML, et al. Androgen signaling is a confounding factor for beta-catenin-mediated prostate tumorigenesis. Oncogene. 2016;35:702–14.

    CAS  PubMed  Google Scholar 

  22. Weischenfeldt J, Simon R, Feuerbach L, Schlangen K, Weichenhan D, Minner S, et al. Integrative genomic analyses reveal an androgen-driven somatic alteration landscape in early-onset prostate cancer. Cancer Cell. 2013;23:159–70.

    CAS  PubMed  Google Scholar 

  23. Wang BD, Yang Q, Ceniccola K, Bianco F, Andrawis R, Jarrett T, et al. Androgen receptor-target genes in African American prostate cancer disparities. Prostate Cancer. 2013;2013:763569.

    PubMed  PubMed Central  Google Scholar 

  24. Albertelli MA, Scheller A, Brogley M, Robins DM. Replacing the mouse androgen receptor with human alleles demonstrates glutamine tract length-dependent effects on physiology and tumorigenesis in mice. Mol Endocrinol. 2006;20:1248–60.

    CAS  PubMed  Google Scholar 

  25. Wu X, Wu J, Huang J, Powell WC, Zhang J, Matusik RJ, et al. Generation of a prostate epithelial cell-specific Cre transgenic mouse model for tissue-specific gene ablation. Mech Dev. 2001;101:61–9.

    CAS  PubMed  Google Scholar 

  26. Harada N, Tamai Y, Ishikawa T, Sauer B, Takaku K, Oshima M, et al. Intestinal polyposis in mice with a dominant stable mutation of the beta-catenin gene. Embo J. 1999;18:5931–42.

    CAS  PubMed  PubMed Central  Google Scholar 

  27. Ittmann M, Huang J, Radaelli E, Martin P, Signoretti S, Sullivan R, et al. Animal models of human prostate cancer: the consensus report of the New York Meeting of the Mouse Models of Human Cancers Consortium Prostate Pathology Committee. Cancer Res. 2013;73:2718–36.

    CAS  PubMed  PubMed Central  Google Scholar 

  28. Gann PH, Hennekens CH, Ma J, Longcope C, Stampfer MJ. Prospective study of sex hormone levels and risk of prostate cancer. J Natl Cancer Inst. 1996;88:1118–26.

    CAS  PubMed  Google Scholar 

  29. Zhang L, Zhang B, Han SJ, Shore AN, Rosen JM, Demayo FJ, et al. Targeting CreER(T2) expression to keratin 8-expressing murine simple epithelia using bacterial artificial chromosome transgenesis. Transgenic Res. 2012;21:1117–23.

    CAS  PubMed  PubMed Central  Google Scholar 

  30. Mahmoudi T, Boj SF, Hatzis P, Li VS, Taouatas N, Vries RG, et al. The leukemia-associated Mllt10/Af10-Dot1l are Tcf4/beta-catenin coactivators essential for intestinal homeostasis. PLoS Biol. 2010;8:e1000539.

    PubMed  PubMed Central  Google Scholar 

  31. Dess RT, Hartman HE, Mahal BA, Soni PD, Jackson WC, Cooperberg MR, et al. Association of black race with prostate cancer-specific and other-cause mortality. JAMA Oncol. 2019;5:975–83.

    PubMed  PubMed Central  Google Scholar 

  32. McNamara MA, Oyekunle T, Chin BB, Oldan J, Anand A, Ritz M, et al. Patterns of response and progression in bone and soft tissue during and after treatment with radium-223 for metastatic castrate-resistant prostate cancer. Prostate. 2019;79:1106–16.

    CAS  PubMed  Google Scholar 

  33. Spratt DE, Chen YW, Mahal BA, Osborne JR, Zhao SG, Morgan TM, et al. Individual patient data analysis of randomized clinical trials: impact of black race on castration-resistant prostate cancer outcomes. Eur Urol Focus. 2016;2:532–9.

    PubMed  Google Scholar 

  34. Jenster G. The role of the androgen receptor in the development and progression of prostate cancer. Semin Oncol. 1999;26:407–21.

    CAS  PubMed  Google Scholar 

  35. Irvine RA, Yu MC, Ross RK, Coetzee GA. The CAG and GGC microsatellites of the androgen receptor gene are in linkage disequilibrium in men with prostate cancer. Cancer Res. 1995;55:1937–40.

    CAS  PubMed  Google Scholar 

  36. Yu Z, Dadgar N, Albertelli M, Scheller A, Albin RL, Robins DM, et al. Abnormalities of germ cell maturation and sertoli cell cytoskeleton in androgen receptor 113 CAG knock-in mice reveal toxic effects of the mutant protein. Am J Pathol. 2006;168:195–204.

    CAS  PubMed  PubMed Central  Google Scholar 

  37. Koh CM, Bieberich CJ, Dang CV, Nelson WG, Yegnasubramanian S, De Marzo AM. MYC and prostate cancer. Genes Cancer. 2010;1:617–28.

    CAS  PubMed  PubMed Central  Google Scholar 

  38. Pan H, Zhu Y, Wei W, Shao S, Rui X. Transcription factor FoxM1 is the downstream target of c-Myc and contributes to the development of prostate cancer. World J Surg Oncol. 2018;16:59.

    PubMed  PubMed Central  Google Scholar 

  39. Shukla S, Bhaskaran N, Maclennan GT, Gupta S. Deregulation of FoxO3a accelerates prostate cancer progression in TRAMP mice. Prostate. 2013;73:1507–17.

    CAS  PubMed  PubMed Central  Google Scholar 

  40. Wang J, Place RF, Huang V, Wang X, Noonan EJ, Magyar CE, et al. Prognostic value and function of KLF4 in prostate cancer: RNAa and vector-mediated overexpression identify KLF4 as an inhibitor of tumor cell growth and migration. Cancer Res. 2010;70:10182–91.

    CAS  PubMed  PubMed Central  Google Scholar 

  41. Zheng C, Ren Z, Wang H, Zhang W, Kalvakolanu DV, Tian Z, et al. E2F1 Induces tumor cell survival via nuclear factor-kappaB-dependent induction of EGR1 transcription in prostate cancer cells. Cancer Res. 2009;69:2324–31.

    CAS  PubMed  Google Scholar 

  42. Rennoll S, Yochum G. Regulation of MYC gene expression by aberrant Wnt/beta-catenin signaling in colorectal cancer. World J Biol Chem. 2015;6:290–300.

    PubMed  PubMed Central  Google Scholar 

  43. Fleming WH, Hamel A, MacDonald R, Ramsey E, Pettigrew NM, Johnston B, et al. Expression of the c-myc protooncogene in human prostatic carcinoma and benign prostatic hyperplasia. Cancer Res. 1986;46:1535–8.

    CAS  PubMed  Google Scholar 

  44. Kumar R, Bhat TA, Walsh EM, Chaudhary AK, O’Malley J, Rhim JS, et al. Cytochrome c deficiency confers apoptosome and mitochondrial dysfunction in African-American men with prostate cancer. Cancer Res. 2019;79:1353–68.

    CAS  PubMed  PubMed Central  Google Scholar 

  45. Sugimura Y, Cunha GR, Donjacour AA. Morphological and histological study of castration-induced degeneration and androgen-induced regeneration in the mouse prostate. Biol Reprod. 1986;34:973–83.

    CAS  PubMed  Google Scholar 

  46. Zhu C, Luong R, Zhuo M, Johnson DT, McKenney JK, Cunha GR, et al. Conditional expression of the androgen receptor induces oncogenic transformation of the mouse prostate. J Biol Chem. 2011;286:33478–88.

    CAS  PubMed  PubMed Central  Google Scholar 

  47. Drost J, Karthaus WR, Gao D, Driehuis E, Sawyers CL, Chen Y, et al. Organoid culture systems for prostate epithelial and cancer tissue. Nat Protoc. 2016;11:347–58.

    CAS  PubMed  PubMed Central  Google Scholar 

  48. Lee J, Beliakoff J, Sun Z. The novel PIAS-like protein hZimp10 is a transcriptional co-activator of the p53 tumor suppressor. Nucleic Acids Res. 2007;35:4523–34.

    CAS  PubMed  PubMed Central  Google Scholar 

  49. Kim D, Pertea G, Trapnell C, Pimentel H, Kelley R, Salzberg SL. TopHat2: accurate alignment of transcriptomes in the presence of insertions, deletions and gene fusions. Genome Biol. 2013;14:R36.

    PubMed  PubMed Central  Google Scholar 

  50. Anders S, Pyl PT, Huber W. HTSeq–a Python framework to work with high-throughput sequencing data. Bioinformatics. 2015;31:166–9.

    CAS  PubMed  Google Scholar 

  51. Hsu F, Kent WJ, Clawson H, Kuhn RM, Diekhans M, Haussler D. The UCSC known genes. Bioinformatics. 2006;22:1036–46.

    CAS  PubMed  Google Scholar 

  52. Mortazavi A, Williams BA, McCue K, Schaeffer L, Wold B. Mapping and quantifying mammalian transcriptomes by RNA-Seq. Nat Methods. 2008;5:621–8.

    CAS  PubMed  Google Scholar 

  53. Lawrence M, Huber W, Pages H, Aboyoun P, Carlson M, Gentleman R, et al. Software for computing and annotating genomic ranges. PLoS Comput Biol. 2013;9:e1003118.

    CAS  PubMed  PubMed Central  Google Scholar 

  54. Benjamini Y, Hochberg Y. Controlling the false discovery rate - a practical and powerful approach to multiple testing. J R Stat Soc B. 1995;57:289–300.

    Google Scholar 

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Acknowledgements

This work was supported by Public Health Service grants R01CA070297, R01CA166894, R21CA190021, and R01DK104941.

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Correspondence to Zijie Sun.

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He, Y., Mi, J., Olson, A. et al. Androgen receptor with short polyglutamine tract preferably enhances Wnt/β-catenin-mediated prostatic tumorigenesis. Oncogene 39, 3276–3291 (2020). https://doi.org/10.1038/s41388-020-1214-7

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