CREB5 Promotes Resistance to Androgen-Receptor Antagonists and Androgen Deprivation in Prostate Cancer

Publication date: 19 November 2019Source: Cell Reports, Volume 29, Issue 8Author(s): Justin H. Hwang, Ji-Heui Seo, Michael L. Beshiri, Stephanie W.owicz, David Liu, Alexander Cheung, Ji Li, Xintao Qiu, Andrew L. Hong, Ginevra Botta, Lior Golumb, Camden Richter, Jonathan So, Gabriel J. Sandoval, Andrew O. Giacomelli, Seav Huong Ly, Celine Han, Chao Dai, Hubert Pakula, Anjali SheahanSummaryAndrogen-receptor (AR) inhibitors, including enzalutamide, are used for treatment of all metastatic castration-resistant prostate cancers (mCRPCs). However, some patients develop resistance or never respond. We find that the transcription factor CREB5 confers enzalutamide resistance in an open reading frame (ORF) expression screen and in tumor xenografts. CREB5 overexpression is essential for an enzalutamide-resistant patient-derived organoid. In AR-expressing prostate cancer cells, CREB5 interactions enhance AR activity at a subset of promoters and enhancers upon enzalutamide treatment, including MYC and genes involved in the cell cycle. In mCRPC, we found recurrent amplification and overexpression of CREB5. Our observations identify CREB5 as one mechanism that drives resistance to AR antagonists in prostate cancers.Graphical Abstract
Source: Cell Reports - Category: Cytology Source Type: research