RNA-binding protein DDX3 mediates posttranscriptional regulation of androgen receptor: A mechanism of castration resistance

Abstract

Prostate cancer (CaP) driven by androgen receptor (AR) is treated with androgen deprivation; however, therapy failure results in lethal castration-resistant prostate cancer (CRPC). AR-low/negative (ARL/−) CRPC subtypes have recently been characterized and cannot be targeted by hormonal therapies, resulting in poor prognosis. RNA-binding protein (RBP)/helicase DDX3 (DEAD-box helicase 3 X-linked) is a key component of stress granules (SG) and is postulated to affect protein translation. Here, we investigated DDX3-mediated posttranscriptional regulation of AR mRNA (messenger RNA) in CRPC. Using patient samples and preclinical models, we objectively quantified DDX3 and AR expression in ARL/− CRPC. We utilized CRPC models to identify DDX3:AR mRNA complexes by RNA immunoprecipitation, assess the effects of DDX3 gain/loss-of-function on AR expression and signaling, and address clinical implications of targeting DDX3 by assessing sensitivity to AR-signaling inhibitors (ARSI) in CRPC xenografts in vivo. ARL/− CRPC expressed abundant AR mRNA despite diminished levels of AR protein. DDX3 protein was highly expressed in ARL/− CRPC, where it bound to AR mRNA. Consistent with a repressive regulatory role, DDX3 localized to cytoplasmic puncta with SG marker PABP1 in CRPC. While induction of DDX3-nucleated SGs resulted in decreased AR protein expression, inhibiting DDX3 was sufficient to restore 1) AR protein expression, 2) AR signaling, and 3) sensitivity to ARSI in vitro and in vivo. Our findings implicate the RBP protein DDX3 as a mechanism of posttranscriptional regulation for AR in CRPC. Clinically, DDX3 may be targetable for sensitizing ARL/− CRPC to AR-directed therapies.

Cytoplasmic DDX3 as prognosticator in male breast cancer

“…High AR in ER-positive FBC patients was associated with a better prognosis in a previous study [43] and thus is in line with our findings. This is an interesting finding as in prostate cancer, especially in castration-resistant prostate cancer, high cytoplasmic DDX3 expression was associated with lower AR expression [44]. Either different DDX3 roles in different types of cancer, oncogenic or suppressive, or the small amount of AR measured MBC patients in this study, could be an explanation for these differences.…”

Biomolecular Condensates and Cancer

“…In ARL/negative CRPC cells, the RNA binding protein DDX3 is highly expressed, binds to AR mRNA, and sequesters it in cytoplasmic stress granule condensates, thus limiting its translation. Inhibiting DDX3 was found to be sufficient to restore AR protein expression and sensitivity to AR signaling inhibitors (Vellky et al, 2020). Improved understanding of these mechanisms should lead to more effective strategies to minimize drug resistance for patient benefit.…”

Stress Granules Involved in Formation, Progression and Metastasis of Cancer: A Scoping Review

“…After that, cell culture, animal and human sample studies with 12.5% of studies (Grabocka and Bar-Sagi, 2016;Coppin et al, 2017;Wang et al, 2018;Choi et al, 2019;Vellky et al, 2020;Zhang et al, 2021;Zhao et al, 2021), respectively, cell culture and human sample studies with 10% of the total studies (Andersson et al, 2008;Wen et al, 2012;Cougot et al, 2014;Bartkowiak et al, 2015;Chiou et al, 2017;Lin et al, 2019), cell culture and animal study in 9% of the total studies (Meng et al, 2012;Gupta et al, 2017;Morettin et al, 2017;Chen H.-Y. et al, 2018;Wang et al, 2021), had a share of this study.…”