Tumor-Specific Retrogene NANOGP8 Reprograms Prostate Cancer Cells to Castration Resistance by Engaging the FOXA1/AR Signaling Axis and MYC
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ABSTRACT:
ORGANISM(S): Homo sapiens
PROVIDER: GSE74800 | GEO | 2016/11/08
SECONDARY ACCESSION(S): PRJNA301560
REPOSITORIES: GEO
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Project description:The pluripotency transcription factor NANOG has been implicated in tumor development, and NANOG-expressing cancer cells manifest stem cell properties that sustain tumor homeostasis, mediate therapy resistance and fuel tumor progression. However, how NANOG converges on somatic circuitry to trigger oncogenic reprogramming remains obscure. We previously reported that inducible NANOG expression propels the emergence of aggressive castration-resistant prostate cancer phenotypes. Here we first show that endogenous NANOG is required for the growth of castration-resistant prostate cancer xenografts. Genome-wide chromatin immunoprecipitation sequencing coupled with biochemical assays unexpectedly reveals that NANOG co-occupies a distinctive proportion of androgen receptor/Forkhead box A1 genomic loci and physically interacts with androgen receptor and Forkhead box A1. Integrative analysis of chromatin immunoprecipitation sequencing and time-resolved RNA sequencing demonstrates that NANOG dynamically alters androgen receptor/Forkhead box A1 signaling leading to both repression of androgen receptor-regulated pro-differentiation genes and induction of genes associated with cell cycle, stem cells, cell motility and castration resistance. Our studies reveal global molecular mechanisms whereby NANOG reprograms prostate cancer cells to a clinically relevant castration-resistant stem cell-like state driven by distinct NANOG-regulated gene clusters that correlate with patient survival. Thus, reprogramming factors such as NANOG may converge on and alter lineage-specific master transcription factors broadly in somatic cancers, thereby facilitating malignant disease progression and providing a novel route for therapeutic resistance.
| S-EPMC5109294 | biostudies-literature
Project description:Targeted disruption of the embryonic stem cell (ESC) self-renewal and pluripotency factor NANOG diminishes cancer cell clonogenic growth in vitro and tumor development in vivo. NANOG has also been shown to augment CSC properties and propel the emergence of castration-resistance prostate cancer (CRPC) phenotypes. Here, we investigate the molecular mechanisms underlying NANOG-mediated oncogenesis and prostate cancer progression to androgen independence. ChIP-Seq analysis of LNCaP prostate cancer cells overexpressing doxycycline-inducible NANOG (either NANOG1 or NANOGP8 vs pLVX control) reveal that NANOG coordinately occupies regions of chromatin regulated by AR signaling steroid-receptor complex proteins AR, FOXA1 and NKX3.1. Taken together with the NANOG-induced changes in the prostate cancer transcriptome (RNA-Seq), NANOG appears to reprogram prostate cancer cells to castration resistance by converging on steroid-hormone receptor signaling.
2016-11-08 | GSE74798 | GEO
Project description:Targeted disruption of the embryonic stem cell (ESC) self-renewal and pluripotency factor NANOG has been shown to diminish cancer cell clonogenic growth in vitro and tumor development in vivo. NANOG has also been shown to augment CSC properties and propel the emergence of castration-resistance prostate cancer (CRPC) phenotypes. Here, we investigate the molecular mechanisms underlying NANOG-mediated oncogenesis and prostate cancer progression to androgen independence. ChIP-Seq analysis of LNCaP prostate cancer cells overexpressing doxycycline-inducible NANOG (either NANOG1 or NANOGP8 vs pLVX control) reveal that NANOG coordinately occupies regions of chromatin regulated by AR signaling steroid-receptor complex proteins AR, FOXA1 and NKX3.1. Taken together with the NANOG-induced changes in the prostate cancer transcriptome (RNA-Seq), NANOG appears to reprogram prostate cancer cells to castration resistance by converging on steroid-hormone receptor signaling.
2016-11-08 | GSE74799 | GEO
Project description:Tumor-Specific Retrogene NANOGP8 Reprograms Prostate Cancer Cells to Castration Resistance by Engaging the FOXA1/AR Signaling Axis and MYC
| PRJNA301560 | ENA
Project description:Androgen receptor splice variant 7 (AR-V7), a form of ligand-independent and constitutively activating variant of androgen receptor (AR), is considered as the key driver to initiate castration-resistant prostate cancer (CRPC). Because AR-V7 lacks ligand-binding domain, the AR-targeted therapies that aim to inactivate AR signaling through disrupting the interaction between AR and androgen are limited in CRPC. Thus, the emergence of AR-V7 has become the greatest challenge for treating CRPC. Targeting protein degradation is a recently proposed novel avenue for cancer treatment. Our previous studies have been shown that the oncoprotein AR-V7 is a substrate of the proteasome. Identifying novel drugs that can trigger the degradation of AR-V7 is therefore critical to cure CRPC. Here we show that nobiletin, a polymethoxylated flavonoid derived from the peel of Citrus fruits, exerts a potent anticancer activity via inducing G0/G1 phase arrest and enhancing the sensitivity of cells to enzalutamide in AR-V7 positive PC cells. Mechanically, we unravel that nobiletin selectively induces proteasomal degradation of AR-V7 (but not AR). This effect relies on its selective inhibition of the interactions between AR-V7 and two deubiquitinases USP14 and USP22. These findings not only enrich our understanding on the mechanism of AR-V7 degradation, but also provide an efficient and druggable target for overcoming CRPC through interfering the stability of AR-V7 mediated by the interaction between AR-V7 and deubiquitinase.
| S-EPMC8455663 | biostudies-literature
Project description:BackgroundProgression to a castration resistance state is the main cause of deaths in prostate cancer (PCa) patients. Androgen Receptor (AR) signaling plays the central role in progression of Castration Resistant Prostate Cancer (CRPC), therefore understanding the mechanisms of AR activation in the milieu of low androgen is critical to discover novel approach to treat CRPC.MethodsFirstly, we explore the CRPC associated lncRNAs by transcriptome microarray. The expression and clinical features of lnc-LBCS are analyzed in three independent large-scale cohorts. The functional role and mechanism of lnc-LBCS are further investigated by gain and loss of function assays in vitro.ResultsThe expression of Lnc-LBCS was lower in CRPC cells lines and tissues. LBCS downregulation was correlated with higher Gleason Score, T stage and poor prognosis of PCa patients. LBCS overexpression decreases, whereas LBCS knockdown increases, the traits of castration resistance in prostate cancer cells under androgen ablated or AR blocked condition. Moreover, knockdown of LBCS was sufficient to activate AR signaling in the absence of androgen by elevating the translation of AR protein. Mechanistically, LBCS interacted directly with hnRNPK to suppress AR translation efficiency by forming complex with hnRNPK and AR mRNA.ConclusionsLnc-LBCS functions as a novel AR translational regulator that suppresses castration resistance of prostate cancer by interacting with hnRNPK. This sheds a new insight into the regulation of CRPC by lncRNA mediated AR activation and LBCS-hnRNPK-AR axis provides a promising approach to the treatment of CRPC.
| S-EPMC6585145 | biostudies-literature
Project description:Rationale: Androgen receptor splice variant 7 (AR-V7) is a leading cause of the development of castration-resistant prostate cancer (CRPC). However, the regulation and function of AR-V7 at levels of post-translational modifications in prostate cancer therapy remain poorly understood. Here, we conducted a library screen of natural products to identify potential small molecules responsible for AR-V7 protein degradation in human prostate cancer cell lines. Methods: A natural product library was used to screen the inhibitor of AR-V7. Co-IP and biomass spectrum assays were used to identify the AR-V7-interacting proteins, whereas western blot, confocal microscopy, RNA interfering, and gene transfection were used to validate these interactions. Cell viability, EDU staining, and colony formation assays were employed to detect cell growth and proliferation. Flowcytometry assays were used to detect the distribution of cell cycle. Mouse xenograft models were used to study the anti-CRPC effects in vivo. Results: This screen identified rutaecarpine, one of the major components of the Chinese medicine Evodia rutaecarpa, as a novel chemical that selectively induces AR-V7 protein degradation via K48-linked ubiquitination. Mechanically, this effect relies on rutaecarpine inducing the formation of a GRP78-AR-V7 protein complex, which further recruits the E3 ligase SIAH2 to directly promote the ubiquitination of AR-V7. Consequently, the genetic and pharmacological activation of the GRP78-dependent AR-V7 protein degradation restores the sensitivity of castration-resistant prostate cancer to anti-androgen therapy in cell culture and animal models. Conclusions: These findings not only provide a new approach for overcoming castration-resistance in prostate cancer therapy, but also increase our understanding about the interplay between molecular chaperones and ubiquitin ligase in shaping protein stability.
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Project description:Abiraterone, a novel androgen synthesis inhibitor, has been approved for castration-resistant prostate cancer (CRPC) treatment. However, most patients eventually acquire resistance to this agent, and the underlying mechanisms related to this resistance remain largely unelucidated. Lysine acetyltransferase 2 A (KAT2A) has been reported to enhance transcriptional activity for certain histone or non-histone proteins through the acetylation and post-translational modification of the androgen receptor (AR). Therefore, we hypothesised that KAT2A might play a critical role in the resistance of prostate tumours to hormonal treatment. In this study, we found that KAT2A expression was increased in abiraterone-resistant prostate cancer C4-2 cells (C4-2-AbiR). Consistently, elevated expression of KAT2A was observed in patients with prostate cancer exhibiting high-grade disease or biochemical recurrence following radical prostatectomy, as well as in those with poor clinical survival outcomes. Moreover, KAT2A knockdown partially re-sensitised C4-2-AbiR cells to abiraterone, whereas KAT2A overexpression promoted abiraterone resistance in parental C4-2 cells. Consistent with this finding, KAT2A knockdown rescued abiraterone sensitivity and inhibited the proliferation of C4-2-AbiR cells in a mouse model. Mechanistically, KAT2A directly acetylated the hinge region of the AR, and induced AR translocation from the cytoplasm to the nucleus, resulting in increased transcriptional activity of the AR-targeted gene prostate specific antigen (PSA) leading to resistance to the inhibitory effect of abiraterone on proliferation. Taken together, our findings demonstrate a substantial role for KAT2A in the regulation of post-translational modifications in AR affecting CRPC development, suggesting that targeting KAT2A might be a potential strategy for CRPC treatment.
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Project description:Androgen deprivation therapy (ADT) and novel hormonal agents (NHAs) (Abiraterone and Enzalutamide) are the goal standard for metastatic prostate cancer (PCa) treatment. Although ADT is initially effective, a subsequent castration resistance status (CRPC) is commonly developed. The expression of androgen receptor (AR) alternative splicing isoforms (AR-V7 and AR-V9) has been associated to CRPC. However, resistance mechanisms to novel NHAs are not yet well understood. Androgen-dependent PCa cell lines were used to generate resistant models to ADT only or in combination with Abiraterone and/or Enzalutamide (concomitant models). Functional and genetic analyses were performed for each resistance model by real-time cell monitoring assays, flow cytometry and RT-qPCR. In androgen-dependent PCa cells, the administration of Abiraterone and/or Enzalutamide as first-line treatment involved a critical inhibition of AR activity associated with a significant cell growth inhibition. Genetic analyses on ADT-resistant PCa cell lines showed that the CRPC phenotype was accompanied by overexpression of AR full-length and AR target genes, but not necessarily AR-V7 and/or AR-V9 isoforms. These ADT resistant cell lines showed higher proliferation rates, migration and invasion abilities. Importantly, ADT resistance induced cross-resistance to Abiraterone and/or Enzalutamide. Similarly, concomitant models possessed an elevated expression of AR full-length and proliferation rates and acquired cross-resistance to its alternative NHA as second-line treatment.
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Project description:Metastatic castration-resistant prostate cancers (mCRPCs) are treated with therapies that antagonize the androgen receptor (AR). Nearly all patients develop resistance to AR-targeted therapies (ARTs). Our previous work identified CREB5 as an upregulated target gene in human mCRPC that promoted resistance to all clinically approved ART. The mechanisms by which CREB5 promotes progression of mCRPC or other cancers remains elusive. Integrating ChIP-seq and rapid immunoprecipitation and mass spectroscopy of endogenous proteins, we report that cells overexpressing CREB5 demonstrate extensive reprogramming of nuclear protein-protein interactions in response to the ART agent enzalutamide. Specifically, CREB5 physically interacts with AR, the pioneering actor FOXA1, and other known co-factors of AR and FOXA1 at transcription regulatory elements recently found to be active in mCRPC patients. We identified a subset of CREB5/FOXA1 co-interacting nuclear factors that have critical functions for AR transcription (GRHL2, HOXB13) while others (TBX3, NFIC) regulated cell viability and ART resistance and were amplified or overexpressed in mCRPC. Upon examining the nuclear protein interactions and the impact of CREB5 expression on the mCRPC patient transcriptome, we found that CREB5 was associated with Wnt signaling and epithelial to mesenchymal transitions, implicating these pathways in CREB5/FOXA1-mediated ART resistance. Overall, these observations define the molecular interactions among CREB5, FOXA1, and pathways that promote ART resistance.
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