Abstract 1865: TRIM24 acts as a transcriptional co-activator of the androgen receptor during prostate cancer progression

Abstract

Abstract The steroid hormone androgen mediates a wide range of developmental, physiological and malignant responses by acting as an agonist for the androgen receptor (AR). AR in turn functions as a nuclear receptor transcription factor and executes specific gene expression programs in an androgen-dependent manner. Since the growth of prostate cancer cells initially depends on androgen, cancer therapy uses hormone-deprivation approaches to reduce the levels of androgen. While prostate cancer (PC) initially responds to androgen-ablation, most tumors progress to a castration resistant (CR) state insensitive to treatment. Both the androgen-dependent and the CRPC state depend on AR, which is probably activated by alternative molecular pathways in CRPC in response to low androgen levels. Here, we assessed the role of the transcriptional co-activator TRIM24 in mediating AR-dependent gene expression and growth in our CRPC cell model LNCaP-abl. We observed that knock-down of TRIM24 impairs CRPC cell growth, while TRIM24 and AR physically interact in these cells in the absence of androgen. When we identified TRIM24-dependent gene expression programs by combining genome-wide binding analyses with microarray studies, we found that TRIM24 and AR co-regulated many genes in CRPC cells. TRIM24- and AR-co-activated genes often function in mitosis and their expression is higher in patients with an increased chance of prostate cancer recurrence. These findings are corroborated by IHC-analyses of prostate cancer patients, where higher TRIM24 protein levels correlated with a greater chance of biochemical recurrence, higher Gleason scores and larger tumor sizes. Importantly, TRIM24 staining was positively correlated with AR staining. This supports a model where TRIM24 acts as an important activator of AR in the castration-resistant setting and therefore may harbor therapeutic potential. Citation Format: Anna C. Groner, Jonas de Tribolet-Hardy, Jean-Philippe Theurillat, Peter J. Wild, Myles Brown. TRIM24 acts as a transcriptional co-activator of the androgen receptor during prostate cancer progression. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 1865. doi:10.1158/1538-7445.AM2015-1865