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Article Dans Une Revue Oncotarget Année : 2017

Dual effects of constitutively active androgen receptor and full-length androgen receptor for N-cadherin regulation in prostate cancer

Résumé

Constitutively active androgen receptor (AR) variants have been involved in the expression of mesenchymal markers such as N-cadherin in prostate cancer (PCa). However, the underlying molecular mechanisms remain elusive. It remains unclear, whether N-cadherin gene (CDH2) is a direct transcriptional target of AR variants or whether the observed upregulation is due to indirect effects through additional regulatory factors. Moreover, the specific contribution of full-length AR and AR variants in N-cadherin regulation in PCa has never been explored deeply. To investigate this, we artificially mimicked the co-expression of AR variants together with a full-length AR and performed miRNA-seq, RNA-seq and ChIP assays. Our results were in favor of a direct AR variants action on CDH2. Our data also revealed a distinctive mode of action between full-length AR and AR variants to regulate N-cadherin expression. Both wild type AR and AR variants could interact with a regulatory element in intron 1 of CDH2. However, a higher histone H4 acetylation in this genomic region was only observed with AR variants. This suggests that full-length AR may play an occluding function to impede CDH2 upregulation. Our data further highlighted a negative effect of AR variants on the expression of the endogenous full-length AR in LNCaP. These differences in the mode of action of AR variants and full-length AR for the control of one key gene for prostate cancer progression could be worth considering for targeting AR variants in PCa.

Dates et versions

hal-03677815 , version 1 (24-05-2022)

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Felicie Cottard, Pauline Ould Madi-Berthélémy, Eva Erdmann, Frédérique Schaff-Wendling, Céline Keime, et al.. Dual effects of constitutively active androgen receptor and full-length androgen receptor for N-cadherin regulation in prostate cancer. Oncotarget, 2017, 8 (42), pp.72008-72020. ⟨10.18632/oncotarget.18270⟩. ⟨hal-03677815⟩
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