Androgen receptor with short polyglutamine tract preferably enhances Wnt/β-catenin-mediated prostatic tumorigenesis
| Autor: | Dong-Hoon Lee, Adam Olson, Jiaqi Mi, Joseph Geradts, Erika Hooker, Diane M. Robins, Yongfeng He, Vien Le, Won Kyung Kim, Joseph Aldahl, Zijie Sun, Eun-Jeong Yu |
|---|---|
| Rok vydání: | 2020 |
| Předmět: |
Male
0301 basic medicine Cancer Research Carcinogenesis medicine.drug_class MYC Biology medicine.disease_cause Article Proto-Oncogene Proteins c-myc Mice 03 medical and health sciences Prostate cancer 0302 clinical medicine The androgen receptor Genetics medicine Animals Humans Wnt Signaling Pathway Molecular Biology beta Catenin Cell Proliferation Sequence Analysis RNA Prostate Cancer Prostate Wnt signaling pathway Prostatic Neoplasms β-catenin Polyglutamine tract Androgen medicine.disease Wnt signaling Black or African American Gene Expression Regulation Neoplastic Androgen receptor Disease Models Animal 030104 developmental biology Receptors Androgen 030220 oncology & carcinogenesis Catenin Cancer research Peptides Chromatin immunoprecipitation |
| Zdroj: | Oncogene |
| ISSN: | 1476-5594 0950-9232 |
| Popis: | 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. |
| Databáze: | OpenAIRE |
| Externí odkaz: |
|
Full text from SpringerLink