Transcriptome analysis of Enzalutamide-sensitive and -resistant CWR-R1, C4-2B, and VCaP cells
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ABSTRACT:
ORGANISM(S): Homo sapiens
PROVIDER: GSE290016 | GEO | 2026/02/28
REPOSITORIES: GEO
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Project description:Enzalutamide (ENZ) is an inhibitor of the androgen receptor (AR) widely used in managing castration-resistant prostate cancer (CRPC). AHR was found upregulated in different Enzalutamide-resistant (ENZR) prostate cancer cell lines. Knocking down AHR significantly decreased the growth of CWR-R1ENZR and C4-2BENZR cells. To elucidate the underlying mechanism of AHR-mediated growth, we transcriptionally profiled CWR-R1ENZR and C4-2BENZR cells stably expressing control and two AHR-targeting shRNAs. AHR maintained androgen response in CWR-R1ENZR cells likely through driving the expression of many genes targeted by both the androgen receptor and glucocorticoid receptor. Interestingly, knockding down AHR did not have the same effect in C4-2BENZR cells. Instead of strengthing AR signaling, AHR maintained features of neuroendocrine differentiation, an AR-independent mechanism of ENZ resistance, in C4-2BENZR cells. Our results supported that AHR regulates transcriptional networks promoting ENZ resistance in a lineage-dependent manner and holds great potential as a therapeutic target.
2026-02-28 | GSE289910 | GEO
Project description:Enzalumatide (ENZ) is a widely used second generation nonsteroidal Androgen Receptor inhibitor that is integral in managing castration-resistant prostate cancer (CRPC). However, resistance inevitably develops in months and limits the clinical benefits of ENZ. AHR is commonly upregulated in ENZ-resistant (ENZR) cell lines and is essential for ENZR CRPC growth in vitro and in vivo. Interestingly, the canonical AHR xenobiotic pathway does not seem to play a role. To characterize, for the first time, transcriptional targets of AHR in prostate cancer, we performed ChIP-seq of AHR and H3K9ac, a marker of active chromatin, in CWR-R1ENZR cells. An AHR knockdown cell line is also included to identify the difference of AHR trancriptional action. ChIP-seq results revealed that AHR binds to multiple genes targeted by AR and glucocorticoid receptor (GR), a well-established mechanism bypassing the AR blockade of ENZ. Furthermore, AHR also binds to many marker genes of neuroendocrine (NE) differentiation, a feature indicating AR-independence and clinical aggressiveness in prostate cancer. Together, these results depict AHR as an important regulator of reponses to ENZ in CRPC.
2026-02-28 | GSE289313 | GEO
Project description:Illumina gene array analyses of prostate cancer cell lines that had acquired resistance to Enzalutamide (MDV3100). mRNA analyses of four cell lines (CWR-R1, LAPC-4, LNCaP, and VCAP) cells that were either untreated, treated for 48hrs with Enz (short-term), or continuously grown in Enzalutamide for >6 months.
2016-02-24 | E-GEOD-78201 | biostudies-arrayexpress
Project description:Xenografts are useful in vivo tumour models for investigating cancer progression, therapeutic responses and predicting anti-cancer drug response in patients with cancer of a similar phenotype. We have generated bulk RNA-seq data from LNCaP xenografts of a large and well-annotated prostate cancer progression study, investigating responsiveness and subsequent resistance to therapies targeting the androgen receptor (AR). LNCaP xenograft tumour establishment and initial growth are dependent on androgens in male mice (PRE-CX / pre-castration group). Upon castration, AR activity and tumour growth are suppressed (POST-CX / post-castration group), however, this initial responsiveness to castration reproducibly gives way to castration-resistance (CRPC / castration-resistant prostate cancer). Further treatment of CRPC with the AR targeting drug enzalutamide (ENZ) initially provides a therapeutic response (ENZ Sensitive; ENZS), however, resistance emerges in time (ENZ Resistant; ENZR).
2022-09-07 | GSE211856 | GEO
Project description:Background: The sustained activation of androgen receptor splice variant-7 (AR-V7) is a key factor in the resistance of castration-resistant prostate cancer (CRPC) patients to second-generation anti-androgen (AR) drugs such as enzalutamide (ENZ). The AR/AR-V7 protein is regulated by the E3 ubiquitin ligase STUB1 and a protein complex formed by HSP70. However, the specific mechanism remains elusive. Methods: High-throughput RNA sequencing was employed to detect differentially expressed circular RNAs (circRNAs) in ENZ-resistant and control CRPC cells. The coding potential of circSRCAP was identified through polysome profiling and LC-MS. The function of circSRCAP was validated in vitro and in vivo via gain or loss of function assays. Mechanistic insights were derived from immunoprecipitation analyses. Results: A novel ENZ-resistant circular RNA (circRNA) named circSRCAP has been identified, showing upregulation in ENZ-resistant C4-2B cells (ENZR-C4-2B) and correlation with elevated protein levels of AR-V7. circSRCAP undergoes cleavage into a loop by the splicing factor EIF4A3 and is derived from the nucleus by the RNA helicase DDX39A. Mechanistically, circSRCAP encodes a 75 amino acid peptide, circSRCAP-75aa, which inhibits the ubiquitination of the AR/AR-V7's co-chaperone protein HSP70 by dissociating STUB1, a ubiquitin E3 ligase. This process leads to the upregulation of AR-V7 protein expression, thereby promoting resistance of castration-resistant prostate cancer (CRPC) cells to ENZ. Xenograft tumor models further confirm the role of circSRCAP in CRPC progression and its potential as a therapeutic target for ENZ-resistant CRPC (ENZR-CRPC). Conclusions: circSRCAP presents an epigenetic mechanism that sheds light on the fate determination of AR-V7, offering a promising therapeutic target for the treatment of ENZR-CRPC.
2025-01-29 | GSE264133 | GEO
Project description:Background: Castration-resistant prostate cancer (CRPC), which has developed resistance to next-generation antiandrogens such as enzalutamide (Enz), is a lethal disease. Furthermore, transcriptional regulation by super enhancers (SEs) are crucial for the growth and spread of prostate cancer, as well as drug resistance. The functions of SEs, a significant class of noncoding DNA cis-regulatory elements, have been the subject of numerous recent studies in the field of cancer research. Methods: The goal of this research was to identify SEs associated with Enz resistance in C4-2B cells using chromatin immunoprecipitation-sequencing and cleavage under targets and tagmentation (CUT&Tag). Using HOMER analysis to predict protein-gene binding motifs, we identified master transcription factors (TFs) that may bind to SE sites. Using small interfering RNA, WST-1 assays, and qRT-PCR, we then confirmed the associations between TFs of SEs and Enz resistance. Results: 999 SEs were screened from C4-2B EnzR cells in total. Incorporating analysis with RNA-seq data revealed 46 SEs to be strongly associated with the promotion of Enz resistance. Additionally, we finally predicted that master TFs bind to SEs binding regions. Subsequently, we selected zinc finger protein 467 (ZFP467) and SMAD family member 3 (SMAD3) to confirm the functional connections of master TFs with Enz resistance via SEs (ZNF467). Conclusions: In this study, SMAD3 and ZNF467 found to be closely related to Enz-resistant in CRPC. Our research uncovered a sizable group of SEs linked to Enz resistance in prostate cancer, dissected the mechanisms underlying SE Enz resistance, and shed light on potential clinical uses for SEs.
2025-03-24 | GSE228308 | GEO
Project description:Although AR-targeted therapies (e.g., enzalutamide) initially improve outcomes of prostate cancer (PCa) patients, resistance inevitably develops, driven in part by prostate cancer stem-like cells (PCSCs). However, the molecular mechanisms linking PCSCs maintenance to enzalutamide resistance (ENZR) remain incompletely characterized. The emergence and reversal of ENZR represent critical clinical challenges in PCa therapeutics. Cancer stem-like cells (CSCs) have been implicated in contributing to ENZR through multiple pathways. Here, we demonstrated that CAMK1D, a Ca²⁺/calmodulin-dependent kinase, is consistently upregulated in PCa with ENZR and contributes to resistance by enhancing mitophagy in PCa cells both in vitro and in vivo. Mechanistically, CAMK1D promotes the expansion of PCSCs by enhancing mitophagy through activation of the AMPK-PINK1 signaling pathway, thereby facilitating cellular adaptation. We reveal that CAMK1D interacts with AMPK, triggering lysosomal AMPK activation via metabolic stress–induced PINK1 phosphorylation. This AMPK-PINK1 cascade reprogramsmitochondrial metabolism to fuel PCSCs expansion. In patient-derived xenograft chimeras, targeting mitophagy or CAMK1D-AMPK signaling pathway suppresses tumor growth and depletes the PCSCs population. Our findings establish mitochondrial hemostasis as an important nexus between ENZR and AMPK-mediated PCSCs enrichment in PCa. CAMK1D emerges as a key regulator of ENZR by orchestrating mitophagy-dependent stemness maintenance. Therapeutically, we developed an Enz-siCAM/HNA nanoformulation that potently reverses ENZR and improves treatment responses.
2025-06-30 | GSE299843 | GEO
Project description:We report RNA sequencing data on serial biopsies of prostate cancer VCaP xenografts as the tumors pass from androgen-sensitivity (Pre-Cx), to castration resistance (CRPC, castration resistant prostate cancer), onto resistance to dual therapy with abiraterone plus enzalutamide (AER). From comparison of these RNAseq data sets, we were able to determine differentially expressed genes between the AER/CRPC and Pre-Cx states that could mediate resistance to androgen deprivation therapies.
2018-12-26 | GSE109708 | GEO
Project description:Prostate cancer is the most commonly diagnosed and second-most lethal cancer among men in the United States. The vast majority of prostate cancer deaths are due to castration-resistant prostate cancer (CRPC) â?? the lethal form of the disease that has progressed despite therapies that interfere with activation of androgen receptor (AR) signaling. One emergent resistance mechanism to medical castration is synthesis of intratumoral androgens that activate the AR. This insight led to the development of the AR antagonist enzalutamide. However, resistance to enzalutamide invariably develops, and disease progression is nearly universal. One mechanism of resistance to enzalutamide is an F877L mutation in the AR ligand-binding domain that can convert enzalutamide to an agonist of AR activity. However, mechanisms that contribute to the agonist switch had not been fully clarified, and there were no therapies to block AR F877L. Using cell line models of castration-resistant prostate cancer (CRPC), we determined that cellular androgen content influences enzalutamide agonism of mutant F877L AR. Further, enzalutamide treatment of AR F877L-expressing cell lines recapitulated the effects of androgen activation of F877L AR or wild-type AR. Because the BET bromodomain inhibitor JQ-1 was previously shown to block androgen activation of wild-type AR, we tested JQ-1 in AR F877L-expressing CRPC models. We determined that JQ-1 suppressed androgen or enzalutamide activation of mutant F877L AR and suppressed growth of mutant F877L AR CRPC tumors in vivo, demonstrating a new strategy to treat tumors harboring this mutation. RNA-seq profiles of prostate cancer cell lines to understand gene expression associated with enzalutamide treatment
2016-06-10 | E-GEOD-69896 | biostudies-arrayexpress
Project description:Enzalutamide (ENZ) is a potent androgen receptor (AR) antagonist with activity in castration-resistant prostate cancer (CRPC); however, progression to ENZ-resistant (ENZ-R) CRPC frequently occurs with rising serum PSA levels, implicating AR full length (ARFL) or variants (AR-Vs) in disease progression. To define functional roles of ARFL and AR-Vs in ENZ-R CRPC, we designed 3 antisense oligonucleotides (ASO) targeting exon 1, intron 1, and exon 8 in AR pre-mRNA to knockdown either ARFL alone, or ARFL plus AR-Vs, and examined their respective effects in LNCaP-derived ENZ-R, as well as M12 and 22Rv1, cells. ENZ-R LNCaP xenografts express high levels of both ARFL and AR-V7 compared to CRPC LNCaP xenografts. In particular, ARFL levels were ~20-fold higher than AR-V7. ENZ-R LNCaP sub-lines, derived by selection from the ENZ xenografts, also expressed uniformly high levels of ARFL and AR-V7 compared to CRPC LNCaP cells. In addition, both ARFL and AR-V7 are highly expressed in the nuclear fractions of ENZ-R-LNCaP. In ENZ-R LNCaP cells, knockdown of ARFL alone, or ARFL plus AR-Vs, similarly induced apoptosis, suppressed cell growth and AR-regulated gene expression in vitro, and delayed tumour growth in vivo. In 22Rv1 cells that are inherently resistant to ENZ, knockdown of both ARFL and AR-Vs more potently suppressed cell growth, AR transcriptional activity and AR-regulated gene expression than knockdown of ARFL alone. These data indicate the AR is an important driver of ENZ resistance, and while the contributions of ARFL and AR-Vs can vary across cell systems, ARFL is the key driver in the ENZ-R LNCaP model. AR targeting strategies against both ARFL and AR-Vs is a rational approach for AR-dependent CRPC. CRPC and ENZ-R LNCaP xenografts were generated as described in: Gleave, M.E., et al., Serum prostate specific antigen levels in mice bearing human prostate LNCaP tumors are determined by tumor volume and endocrine and growth factors. Cancer Res, 1992. 52(6): p. 1598-605.
2015-01-01 | GSE55345 | GEO