Abstract 950: Orphan nuclear receptor DAX1 exhibits suppressive effect on prostate cancer cell growth

Abstract

Abstract The nuclear receptor superfamily comprises a large group of transcriptional factors involved broadly in many physiological functions including control of embryonic development and cellular homeostasis. In general, nuclear receptors can bind to specific DNA regulatory elements (REs) as homo- or heterodimers. DAX1 (Dosage sensitive sex reversal (DSS), adrenal hypoplasia congenita (AHC) critical region, on chromosome X, gene 1, NR0B1) is a unique ligand-independent orphan nuclear receptor, which lacks the conventional DNA-binding domain (DBD) and in some cases it functions as a coregulatory protein inhibiting the transcriptional activity of other nuclear receptors by forming heterodimers. Previous studies show that DAX1 may play an essential role in establishment and maintenance of the steroidogenic axis of development, maintenance of murine embryonic stem cell pluripotency and cancer development including ovarian, breast and endometrial cancers. A recent report identified the inverse correlation of immunoreactivity of DAX1 with Gleason score of prostate cancer. In a preliminary investigation of expression patterns of members of nuclear receptor superfamily in a panel of immortalized prostatic epithelial cell and prostate cancer cell lines by semi-quantitative and real-time PCR, we observed that DAX1 displayed a variable expression pattern with low or undetectable levels in most tested immortalized prostatic epithelial cell lines and prostate cancer cell lines (including the classical LNCaP and PC-3) but high levels in some prostate cancer cells (VCaP, DuCaP, RC-58T and DU145) and also an in vitro model of transformed immortalized human prostatic epithelial cells BPH-1CAFTD. In order to elucidate the possible functional roles of DAX1 in the prostate cancer cell growth regulation, we generated DAX1-stable expression clones in two prostate cancer cell lines, LNCaP and PC-3, which expressed low endogenous DAX1 levels, by retroviral transduction for in vitro growth characterization. Our results showed that overexpression of DAX1 in LNCaP and PC-3 cells suppressed their in vitro cell proliferation, single-cell colony formation and anchorage-independent growth capacity in soft agar. Moreover, luciferase reporter gene assay showed that DAX1 suppressed the ERRα-induced transactivation of VEGFA. Our results suggested that DAX1 might perform a suppressive growth regulatory role in prostate cancer cells. (Lin Jia is supported by a RGC Hong Kong-PhD Fellowship Scheme) Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 950. doi:1538-7445.AM2012-950