Basic helix loop helix (bHLH) transcription factor 3 (TCF3, E2A) is regulated by androgens in prostate cancer cells

American Journal of Cancer Research

Divya Patel¹ 

关键词: E2A;    TCF3;    bHLH;    prostate cancer;    androgen receptor;    transcriptional regulation;   

DOI  :  

学科分类：肿瘤学

来源: e-Century Publishing Corporation

【 摘 要 】

TCF3 (E2A) is a multifunctional basic helix loop helix (bHLH) transcription factor that is over-expressed in prostate cancer (PCa) as compared to normal prostate and that it acts as a tumor promoter in PCa. Given the diverse biological pathways regulated/influenced by TCF3, little is known about the mechanisms that regulate its expression. TCF3 expression in androgen sensitive LNCaP and insensitive C81 PCa cell lines was determined following treatments with androgen receptor (AR) agonist R1881 and antagonist Casodex. In silico analysis was used to discover putative Androgen Response Elements (ARE) in the TCF3 promoter/intron region. Chromatin Immunoprecipitation (ChIP) with AR antibody and luciferase reporter assays on the above mentioned cell lines was used to confirm AR biding and AR dependent transcriptional activity respectively. The results were confirmed by demonstrating TCF3 expression in LNCaP PCa xenograft models. The results suggested that TCF3 transcript increased in response to R1881 in LNCaP cells but was constitutively expressed in C-81 cell lines. The promoter/Intron region of the TCF3 gene was predicted to contain two putative ARE sites ARE1 and ARE2. ChIP after treatment of LNCaP and C81 cells with R1881 and Casodex showed that the ARE1 and ARE2 were bound by AR in LNCaP cells only in the presence of R1881, whereas C81 cells showed constitutive AR binding. Similar results were observed in luciferase reporter assays indicating that TCF3 is activated by AR in LNCaP cell lines whereas it is independent of androgens in C81 cell line. Luciferase reporter assays also confirmed that ARE1 alone drives androgen dependent transcription. TCF3 expression was only observed in castration resistant LNCaP xenografts in castrated mice. In conclusion, we demonstrate that in PCa androgen receptor regulates the expression of TCF3 which is mediated in part via a consensus androgen response element. The shift in TCF3 expression from androgen regulated to androgen independent during prostate cancer progression, together with lack of expression in normal prostate may provide mechanistic basis underlying the transition of androgen receptor from a tumor suppressor to an oncogene in prostate cancer.

【 授权许可】

CC BY-NC