Men presenting with advanced prostate cancer that has spread beyond the prostate are increasingly being considered for treatments directed at the prostate itself. On the basis of results for our international series of 106 men, surgery appears reasonably safe in this setting for certain patients.
Based on this systematic review, there is no strong evidence to support one therapy over another as EBRT, BT and RP can all be considered as effective monotherapies for localised disease with EBRT also effective for post-operative management. All treatments have unique adverse events profiles. Further large, robust RCTs which report treatment-specific and treatment combination-specific outcomes in defined prostate cancer risk groups following established reporting standards are needed. These will strengthen the evidence base for newer technologies, help reinforce current consensus guidelines and establish greater standardisation across practices.
The androgen receptor (AR) is required for prostate cancer (PCa) survival and progression, and ablation of AR activity is the first line of therapeutic intervention for disseminated disease. While initially effective, recurrent tumors ultimately arise for which there is no durable cure. Despite the dependence of PCa on AR activity throughout the course of disease, delineation of the AR-dependent transcriptional network that governs disease progression remains elusive, and the function of AR in mitotically active cells is not well understood. Analyzing AR activity as a function of cell cycle revealed an unexpected and highly expanded repertoire of AR-regulated gene networks in actively cycling cells. New AR functions segregated into two major clusters: those that are specific to cycling cells and retained throughout the mitotic cell cycle (“Cell Cycle Common”), versus those that were specifically enriched in a subset of cell cycle phases (“Phase Restricted”). Further analyses identified previously unrecognized AR functions in major pathways associated with clinical PCa progression. Illustrating the impact of these unmasked AR-driven pathways, dihydroceramide-desaturase 1 (DEGS1) was identified as an AR regulated gene in mitotically active cells that promoted pro-metastatic phenotypes, and in advanced PCa proved to be highly associated with development of metastases, recurrence after therapeutic intervention, and reduced overall survival. Taken together, these findings delineate AR function in mitotically active tumor cells, thus providing critical insight into the molecular basis by which AR promotes development of lethal PCa and nominate new avenues for therapeutic intervention.
Enzalutamide is a second-generation anti-androgen for treatment of castration-resistant prostate cancer (CPRC). It prolongs survival of CRPC patients, but its overall survival benefit is relatively modest (4.8 months) and by 24 months most patients progress on enzalutamide. To date, however, the molecular mechanisms underlying enzalutamide resistance remain elusive. Herein, we report enzalutamide treatment-induced alterations of androgen receptor (AR)-regulated enhancer RNAs (AR-eRNAs) and their roles in enzalutamide-resistant growth and survival of CRPC cells. AR chromatin immunoprecipitation and high throughput sequencing (ChIP-seq) and RNA-seq analyses revealed that 188 and 227 AR-eRNAs were differentially expressed in enzalutamide-resistant LNCaP and C4-2 cells, respectively. The AR-eRNAs upregulated in C4-2 cells and downregulated in LNCaP cells were selected through meta-analysis. Expression of AR-eRNAs and related mRNAs in the loci of FTO, LUZP2, MARC1 and NCAM2 were further verified by real-time RT-PCR. Silencing of LUZP2 inhibited, but silencing of MARC1 increased the growth of enzalutamide-resistant C4-2 cells. Intriguingly, meta-analysis showed that expression of LUZP2 mRNA increased in primary tumors compared to normal prostate tissues, but decreased again in metastatic CRPC. Our findings suggest that eRNA alteration profiling is a viable new approach to identify functional gene loci that may not only contribute to enzalutamide-resistant growth of CRPC, but also serve as new targets for CRPC therapy.
De novo fatty acid (FA) synthesis is required for prostate cancer (PCa) survival and progression. As a key enzyme for FA synthesis fatty acid synthase (FASN) is often overexpressed in human prostate cancers and its expression correlates with worse prognosis and poor survival. P300 is an acetyltransferase that acts as a transcription co-activator. Increasing evidence suggests that P300 is a major PCa promoter, although the underlying mechanism remains poorly understood. Here, we demonstrated that P300 binds to and increases histone H3 lysine 27 acetylation (H3K27Ac) in the FASN gene promoter. We provided evidence that P300 transcriptionally upregulates FASN expression and promotes lipid accumulation in human PCa cells in culture and Pten knockout prostate tumors in mice. Pharmacological inhibition of P300 decreased FASN expression and lipid droplet accumulation in PCa cells. Immunohistochemistry analysis revealed that expression of P300 protein positively correlates with FASN protein levels in a cohort of human PCa specimens. We further showed that FASN is a key mediator of P300-induced growth of PCa cells in culture and in mice. Together, our findings demonstrate P300 as a key factor that regulates FASN expression, lipid accumulation and cell growth in PCa. They also suggest that this regulatory pathway can serve as a new therapeutic target for PCa treatment.
scite is a Brooklyn-based organization that helps researchers better discover and understand research articles through Smart Citations–citations that display the context of the citation and describe whether the article provides supporting or contrasting evidence. scite is used by students and researchers from around the world and is funded in part by the National Science Foundation and the National Institute on Drug Abuse of the National Institutes of Health.