Prostate cancer (CaP) remains the second leading cause of cancer deaths in Western men. These deaths occur because metastatic CaP acquires resistance to available treatments. The novel and functionally diverse treatment options that have been introduced in the clinic over the past decade each eventually induce resistance for which the molecular basis is diverse. Both initiation and progression of CaP have been associated with enhanced cell proliferation and cell cycle dysregulation. A better understanding of the specific pro-proliferative molecular shifts that control cell division and proliferation during CaP progression may ultimately overcome treatment resistance. Here, we examine literature for support of this possibility. We start by reviewing recently renewed insights in prostate cell types and their proliferative and oncogenic potential. We then provide an overview of the basic knowledge on the molecular machinery in charge of cell cycle progression and its regulation by well-recognized drivers of CaP progression such as androgen receptor and retinoblastoma protein. In this respect, we pay particular attention to interactions and reciprocal interplay between cell cycle regulators and androgen receptor. Somatic alterations that impact the cell cycle-associated and -regulated genes encoding p53, PTEN and MYC during progression from treatment-naïve, to castration-recurrent, and in some cases, neuroendocrine CaP are discussed. We considered also non-genomic events that impact cell cycle determinants, including transcriptional, epigenetic and micro-environmental switches that occur during CaP progression. Finally, we evaluate the therapeutic potential of cell cycle regulators and address challenges and limitations in the approaches modulating their action for CaP treatment.

Standard treatment for metastatic prostate cancer (CaP) prevents ligand-activation of androgen receptor (AR). Despite initial remission, CaP progresses while relying on AR. AR transcriptional output controls CaP behavior and is an alternative therapeutic target, but its molecular regulation is poorly understood. Here, we show that action of activated AR partitions into fractions that are controlled preferentially by different coregulators. In a 452-AR-target gene panel, each of 18 clinically relevant coregulators mediates androgen-responsiveness of 0–57% genes and acts as a coactivator or corepressor in a gene-specific manner. Selectivity in coregulator-dependent AR action is reflected in differential AR binding site composition and involvement with CaP biology and progression. Isolation of a novel transcriptional mechanism in which WDR77 unites the actions of AR and p53, the major genomic drivers of lethal CaP, to control cell cycle progression provides proof-of-principle for treatment via selective interference with AR action by exploiting AR dependence on coregulators.

Androgen receptor (AR) is a ligand-activated transcription factor that is the main target for treatment of non-organ-confined prostate cancer (CaP). Failure of life-prolonging AR-targeting androgen deprivation therapy is due to flexibility in steroidogenic pathways that control intracrine androgen levels and variability in the AR transcriptional output. Androgen biosynthesis enzymes, androgen transporters and AR-associated coregulators are attractive novel CaP treatment targets. These proteins, however, are characterized by multiple transcript variants and isoforms, are subject to genomic alterations, and are differentially expressed among CaPs. Determining their therapeutic potential requires evaluation of extensive, diverse datasets that are dispersed over multiple databases, websites and literature reports. Mining and integrating these datasets are cumbersome, time-consuming tasks and provide only snapshots of relevant information. To overcome this impediment to effective, efficient study of AR and potential drug targets, we developed the Regulators of Androgen Action Resource (RAAR), a non-redundant, curated and user-friendly searchable web interface. RAAR centralizes information on gene function, clinical relevance, and resources for 55 genes that encode proteins involved in biosynthesis, metabolism and transport of androgens and for 274 AR-associated coregulator genes. Data in RAAR are organized in two levels: (i) Information pertaining to production of androgens is contained in a ‘pre-receptor level’ database, and coregulator gene information is provided in a ‘post-receptor level’ database, and (ii) an ‘other resources’ database contains links to additional databases that are complementary to and useful to pursue further the information provided in RAAR. For each of its 329 entries, RAAR provides access to more than 20 well-curated publicly available databases, and thus, access to thousands of data points. Hyperlinks provide direct access to gene-specific entries in the respective database(s). RAAR is a novel, freely available resource that provides fast, reliable and easy access to integrated information that is needed to develop alternative CaP therapies. Database URL : http://www.lerner.ccf.org/cancerbio/heemers/RAAR/search/

Prostate cancer (PCa) progression relies on androgen receptor (AR) action. Preventing AR's ligand-activation is the frontline treatment for metastatic PCa. Androgen deprivation therapy (ADT) that inhibits AR ligand-binding initially induces remission but eventually fails, mainly because of adaptive PCa responses that restore AR action. The vast majority of castration-resistant PCa (CRPC) continues to rely on AR activity. Novel therapeutic strategies are being explored that involve targeting other critical AR domains such as those that mediate its constitutively active transactivation function, its DNA binding ability, or its interaction with co-operating transcriptional regulators. Considerable molecular and clinical variability has been found in AR's interaction with its ligands, DNA binding motifs, and its associated coregulators and transcription factors. Here, we review evidence that each of these levels of AR regulation can individually and differentially impact transcription by AR. In addition, we examine emerging insights suggesting that each can also impact the other, and that all three may collaborate to induce gene-specific AR target gene expression, likely via AR allosteric effects. For the purpose of this review, we refer to the modulating influence of these differential and/or interdependent contributions of ligands, cognate DNA-binding motifs and critical regulatory protein interactions on AR's transcriptional output, which may influence the efficiency of the novel PCa therapeutic approaches under consideration, as co-regulation of AR activity.

Prostate cancer (CaP) remains the second leading cause of cancer deaths in western men. CaP mortality results from diverse molecular mechanisms that mediate resistance to the standard of care treatments for metastatic disease. Recently, alternative splicing has been recognized as a hallmark of CaP aggressiveness. Alternative splicing events cause treatment resistance and aggressive CaP behavior and are determinants of the emergence of the two major types of late-stage treatment-resistant CaP, namely castration-resistant CaP (CRPC) and neuroendocrine CaP (NEPC). Here, we review recent multi-omics data that are uncovering the complicated landscape of alternative splicing events during CaP progression and the impact that different gene transcript isoforms can have on CaP cell biology and behavior. We discuss renewed insights in the molecular machinery by which alternative splicing occurs and contributes to the failure of systemic CaP therapies. The potential for alternative splicing events to serve as diagnostic markers and/or therapeutic targets is explored. We conclude by considering current challenges and promises associated with splicing-modulating therapies, and their potential for clinical translation into CaP patient care.