Summary Adenosine-to-inosine RNA editing is crucial for generating molecular diversity, and serves to regulate protein function through recoding of genomic information. Here, we discover editing within CaV1.3 Ca2+ channels, renown for low-voltage Ca2+-influx and neuronal pacemaking. Significantly, editing occurs within the channel’s IQ domain, a calmodulin-binding site mediating inhibitory Ca2+-feedback (CDI) on channels. The editing turns out to require RNA adenosine deaminase ADAR2, whose variable activity could underlie a spatially diverse pattern of CaV1.3 editing seen across the brain. Edited CaV1.3 protein is detected both in brain tissue and within the surface membrane of primary neurons. Functionally, edited CaV1.3 channels exhibit strong reduction of CDI; in particular, neurons within the suprachiasmatic nucleus show diminished CDI, with higher frequencies of repetitive action-potential and calcium-spike activity, in wildtype versus ADAR2 knockout mice. Our study reveals a mechanism for fine-tuning CaV1.3 channel properties in CNS, which likely impacts a broad spectrum of neurobiological functions.

: The human genome is mostly transcribed, yielding a rich repository of noncoding transcripts that are involved in a myriad of biological processes including cancer. However, how many noncoding transcripts such as long noncoding RNAs (lncRNA) function in cancer is still unclear. This study identified a novel set of clinically relevant androgen-regulated lncRNAs in prostate cancer. Among this group, was demonstrated to be a direct androgen-regulated target that is actively transcribed in androgen receptor (AR)-dependent prostate cancer cells. The expression of is higher in normal prostate compared with malignant and metastatic prostate cancer clinical specimens, and patients with low expression had a poor prognosis and significantly increased biochemical recurrence, suggesting functions in suppressing tumor progression and metastasis. Indeed, loss-of-function studies revealed that prevents prostate cancer cell migration and invasion. Moreover, findings from gene expression profiling analysis indicated that functions in , affecting global androgen-regulated gene transcription. Mechanistic evidence reveals that is important in facilitating AR binding to the chromatin. Finally, mediates its phenotypic effects in part by activating the expression of, a crucial cancer metastasis suppressor. Collectively, is a novel coregulator of AR that plays a central role in the androgen transcriptional network and the development and progression of prostate cancer. IMPLICATIONS: This study highlights the function of the lncRNA,, in regulating global AR-regulated genes in prostate cancer by modulating AR binding to chromatin.

The aberrant activities of transcription factors such as the androgen receptor (AR) underpin prostate cancer development. While the AR cis-regulation has been extensively studied in prostate cancer, information pertaining to the spatial architecture of the AR transcriptional circuitry remains limited. In this paper, we propose a novel framework to profile long-range chromatin interactions associated with AR and its collaborative transcription factor, erythroblast transformation-specific related gene (ERG), using chromatin interaction analysis by paired-end tag (ChIA-PET). We identified ERG-associated long-range chromatin interactions as a cooperative component in the AR-associated chromatin interactome, acting in concert to achieve coordinated regulation of a subset of AR target genes. Through multifaceted functional data analysis, we found that AR-ERG interaction hub regions are characterized by distinct functional signatures, including bidirectional transcription and cotranscription factor binding. In addition, cancer-associated long noncoding RNAs were found to be connected near protein-coding genes through AR-ERG looping. Finally, we found strong enrichment of prostate cancer genome-wide association study (GWAS) single nucleotide polymorphisms (SNPs) at AR-ERG co-binding sites participating in chromatin interactions and gene regulation, suggesting GWAS target genes identified from chromatin looping data provide more biologically relevant findings than using the nearest gene approach. Taken together, our results revealed an AR-ERG-centric higher-order chromatin structure that drives coordinated gene expression in prostate cancer progression and the identification of potential target genes for therapeutic intervention.

Nuclear receptor (NR)-mediated transcriptional activity is a dynamic process that is regulated by the binding of ligands that induce distinct conformational changes in the NR. These structural alterations lead to the differential recruitment of coregulators (coactivators or corepressors) that control the expression of NR-regulated genes. Here, we show that a stretch of proline residues located within the N-terminus of androgen receptor (AR) is a bona fide coregulator binding surface, the disruption of which reduces the androgen-dependent proliferation and migration of prostate cancer (PCa) cells. Using T7 phage display, we identified a novel AR-interacting protein, Src homology 3 (SH3)-domain containing, Ysc84-like 1 (SH3YL1), whose interaction with the receptor is dependent upon this polyproline domain. As with mutations within the AR polyproline domain, knockdown of SH3YL1 attenuated androgen-mediated cell growth and migration. RNA expression analysis revealed that SH3YL1 was required for the induction of a subset of AR-modulated genes. Notable was the observation that ubinuclein 1 (UBN1), a key member of a histone H3.3 chaperone complex, was a transcriptional target of the AR/SH3YL1 complex, correlated with aggressive PCa in patients, and was necessary for the maximal androgen-mediated proliferation and migration of PCa cells. Collectively, these data highlight the importance of an amino-terminal activation domain, its associated coregulator, and downstream transcriptional targets in regulating cellular processes of pathological importance in PCa.

Androgen and the androgen receptor (AR) are critical effectors of prostate cancer. Consequently, androgen deprivation therapy is typically employed as a first-line treatment for prostate cancer patients. While initial responses are generally positive, prostate tumors frequently recur and progress to a lethal form known as castration-resistant prostate cancer (CRPC). Recently, considerable effort has been directed toward elucidating the molecular mechanisms of CRPC. Results from both preclinical and clinical studies suggest that AR-mediated signaling persists and remains functionally important in CRPC despite the elimination of androgens. Understanding the role of this pathway in the development of resistance will therefore be critical to identify alternative diagnostic markers as well as more effective therapies for the treatment of CRPC. Using next-generation sequencing and other high-throughput approaches, numerous groups are beginning to identify the key differences in the transcriptional regulatory and gene expression programs between androgen-dependent and CRPC. A number of mechanisms have been proposed for the differences and these mostly involve alterations to components of the AR co-regulatory network. In this review, we summarize current knowledge on co-regulators of the AR and discuss their potential roles in CRPC. It is anticipated that a deeper understanding of these factors will undercover new targets that can assist in the diagnosis and treatment of CRPC.