Targeting DNMTs to overcome enzalutamide resistance in prostate cancer
Ontology highlight
ABSTRACT:
PROVIDER: PRJNA763500 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR15903739_1.fastq.gz | Fastqsanger.gz | |||
| SRR15903739_2.fastq.gz | Fastqsanger.gz | |||
| SRR15903740_1.fastq.gz | Fastqsanger.gz | |||
| SRR15903740_2.fastq.gz | Fastqsanger.gz | |||
| SRR15903741_1.fastq.gz | Fastqsanger.gz |
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Project description:Prostate cancer is the second leading cause of cancer death among men in the United States. The androgen receptor (AR) antagonist enzalutamide is a FDA-approved drug for treatment of patients with late-stage prostate cancer and is currently under clinical study for early-stage prostate cancer treatment. After a short positive response period to enzalutamide, tumors will develop drug resistance. In this study, we uncovered that DNA methylation was deregulated in enzalutamide-resistant cells. DNMT activity and DNMT3B expression were upregulated in resistant cell lines. Enzalutamide induced the expression of DNMT3A and DNMT3B in prostate cancer cells with a potential role of p53 and pRB in this process. The overexpression of DNMT3B3, a DNMT3B variant, promoted an enzalutamide-resistant phenotype in C4-2B cell lines. Inhibition of DNA methylation and DNMT3B knockdown induced a re-sensitization to enzalutamide. Decitabine treatment in enzalutamide-resistant cells induced a decrease of the expression of AR-V7 and changes of genes for apoptosis, DNA repair and mRNA splicing. Combination treatment of Decitabine and enzalutamide induced a decrease of tumor weight, Ki-67 and AR-V7 expression and an increase of cleaved-caspase3 levels in 22Rv1 xenografts. The collective results suggest that DNA methylation pathway is deregulated after enzalutamide resistance onset and that targeting DNA methyltransferases restores the sensitivity to enzalutamide in prostate cancer cells.
2021-09-22 | GSE184168 | GEO
Project description:Prostate cancer is the second leading cause of cancer death among men in the United States. The androgen receptor (AR) antagonist enzalutamide is an FDA-approved drug for treatment of patients with late-stage prostate cancer and is currently under clinical study for early-stage prostate cancer treatment. After a short positive response period to enzalutamide, tumors will develop drug resistance. In this study, we uncovered that DNA methylation was deregulated in enzalutamide-resistant cells. DNMT activity and DNMT3B expression were upregulated in resistant cell lines. Enzalutamide induced the expression of DNMT3A and DNMT3B in prostate cancer cells with a potential role of p53 and pRB in this process. The overexpression of DNMT3B3, a DNMT3B variant, promoted an enzalutamide-resistant phenotype in C4-2B cell lines. Inhibition of DNA methylation and DNMT3B knockdown induced a resensitization to enzalutamide. Decitabine treatment in enzalutamide-resistant cells induced a decrease of the expression of AR-V7 and changes of genes for apoptosis, DNA repair, and mRNA splicing. Combination treatment of decitabine and enzalutamide induced a decrease of tumor weight, Ki-67 and AR-V7 expression and an increase of cleaved-caspase3 levels in 22Rv1 xenografts. The collective results suggest that DNA methylation pathway is deregulated after enzalutamide resistance onset and that targeting DNA methyltransferases restores the sensitivity to enzalutamide in prostate cancer cells.
| S-EPMC8742787 | biostudies-literature
Project description:Enzalutamide, a second-generation androgen receptor (AR) antagonist, has represented the association with improved overall survival in men with prostate cancer (PCa). However, PCa patients receiving enzalutamide will eventually develop resistance through various mechanisms without effective regimens. Here, we observed a higher level of formin-like 2 (FMNL2) in enzalutamide-resistant PCa cells. Functionally, FMNL2 knockdown partially re-sensitized enzalutamide-resistant PCa cells. Mechanistically, FMNL2 directly interacted with SRC kinase through FMNL2-FH1 and SRC-SH3 domain, which induced AR translocation from the cytoplasm to the nucleus, resulting in increased expression of the AR-targeted genes and leading to resistance to enzalutamide. Consistently, SRC inhibitor dasatinib rescued enzalutamide sensitivity and inhibited the proliferation of enzalutamide-resistant cancer cells. Taken together, our findings demonstrate a substantial role for FMNL2/SRC interaction in the regulation of AR translocation, suggesting that targeting FMNL2-mediated SRC activation might be a potential therapeutic strategy for enzalutamide-resistant PCa, and dasatinib could be an option.
2025-01-13 | PXD059539 | Pride
Project description:Utilizing a kinome-wide CRISPR-Cas9 knockout screen, we identified casein kinase 1 alpha (CK1α) as a novel therapeutic target to overcome enzalutamide resistance. To dissect the underlying mechanisms of targeting CK1α to sensitize cancer cells to ENZA, we performed RNA sequencing of 22Rv1 cells upon CK1α knockout or overexpression. We found that CK1α regulated double-strand break (DSB)-response signaling.
2023-03-10 | GSE203362 | GEO
Project description:Prostate cancer C4-2B cells were cultured in enzalutamide in a dose-escalation manner. After sixty passages cells were resistant to enzalutamide, with a specific sets of genes been deregulated. We performed global gene expression analysis by cDNA microarrays to identify genes responsible for enzalutamide resistance in C4-2B-MDVR cells. Enzalutamide resistant C4-2B-MDVR cells were selected from C4-2B cells during long time enzalutamide treatment. Genes responsible for enzalutamide resistance were identified using C4-2B vs. C4-2B-MDVR RNA extraction and hybridization on Affymetrix microarrays.
2015-04-09 | E-GEOD-64143 | biostudies-arrayexpress
Project description:Enzalutamide, a second-generation androgen receptor inhibitor, is utilized for treating patients with metastatic castration-resistant prostate cancer (mCRPC). However, acquired resistance to enzalutamide presents a significant clinical challenge, necessitating novel strategies for overcoming this resistance. In this study, we demonstrated that PLK1 phosphorylates PDCD4 at serine 239 (S239), leading to PDCD4 degradation by enhancing its binding to βTRCP2, thereby promoting enzalutamide resistance both in vitro and in vivo. Mechanistically, phosphorylation of PDCD4 at S239 upregulates the expression of UDP-glucuronosyltransferase 2B15 (UGT2B15) through activation of the c-MYC-Hedgehog axis. This pathway circumvents the androgen receptor, thereby reducing cellular sensitivity to enzalutamide treatment. Inhibition of UGT2B15 enhances enzalutamide-induced cell apoptosis and growth arrest in a manner dependent on PDCD4-S239 phosphorylation. Our findings provide a insight into the role of PLK1-mediated PDCD4 phosphorylation in enzalutamide resistance and suggest a potential therapeutic strategy to overcome resistance in prostate cancer.
2025-04-16 | GSE281361 | GEO
Project description:Analysis of enzalutamide- and/or olaparib-responsive gene expression in prostate cancer cells. The hypothesis tested in the present study was that enzalutamide influences the expression of genes that are involved in important bioprocesses in prostate cance rcells, including DNA damage response genes and this effect may synergize with poly(ADP-ribose) polymerase inhibitor olaparib in cytotoxicity to prstate cancer cells. prostate cancer cells were pretreated with enzalutamide or vehicle control DMSO for 24 h, followed by treatment with enzalutamide, olaparib, enzalutamide+olaparib, or vehicle control DMSO for 48 h. Gene expression in enzalutamide+olaparib-treated cells was compared with taht in vehicle control- and single agent-treated cells.
2016-07-03 | E-GEOD-69249 | biostudies-arrayexpress
Project description:In 2012, the US Food and Drug Administration approved enzalutamide (Xtandi) for the treatment of patients with metastatic castration-resistant prostate cancer who have previously received docetaxel. In most patients, enzalutamide halts progression of the disease for a short period of time, but patients usually relapse, which is associated with poor prognosis. Identifying the genes and pathways that the cancer cells use to overcome enzalutamide are of interest, because new interventions aimed at preventing relapse after enzalutamide therapy would have therapeutic value to late-stage prostate cancer patients. In this study, we took advantage of RNA interference techniques and an in vitro model of castration-resistant prostate cancer cells to identify genes that drive resistance to enzalutamide.
2021-01-10 | GSE156816 | GEO
Project description:To investigate the mechanisms of drug resistance and castration resistance in prostate cancer, we performed proteomic sequencing on androgen-dependent prostate cancer cells (LNCaP) and androgen-independent cells (AI) treated with enzalutamide.
2024-11-26 | PXD058261 |
Project description:Enzalutamide, a second-generation androgen receptor (AR) antagonist, has demonstrated clinical benefit in men with prostate cancer. However, it only provides a temporary response and modest increase in survival, indicating a rapid evolution of resistance. Previous studies suggest that enzalutamide may function as a partial transcriptional agonist, but the underlying mechanisms for enzalutamide-induced transcription remain poorly understood. Here, we show that enzalutamide stimulates expression of a novel subset of genes distinct from androgen-responsive genes. Treatment of prostate cancer cells with enzalutamide enhances recruitment of pioneer factor GATA2, AR, Mediator subunits MED1 and MED14, and RNA Pol II to regulatory elements of enzalutamide-responsive genes. Mechanistically, GATA2 functions in directing AR, Mediator and Pol II loading to enzalutamide-responsive gene loci. Importantly, the GATA2 inhibitor K7174 inhibits enzalutamide-induced transcription by decreasing binding of the GATA2/AR/Mediator/Pol II transcriptional complex, contributing to sensitization of prostate cancer cells to enzalutamide treatment. Our findings provide mechanistic insight into the future combination of GATA2 inhibitors and enzalutamide for improved AR-targeted therapy.
2019-09-03 | GSE125014 | GEO