Dataset Information

FOXJ1 regulates microtubule dynamics in nonciliated cells and is a mediator of taxane resistance

ABSTRACT: Docetaxel is the first-line chemotherapy for metastatic castration-resistant prostate cancer (PC) and taxanes are broadly used in other cancers, but mechanisms of resistance remain to be established. In our study, we generated docetaxel-resistant PC xenografts and found increased expression of genes that drive development of multiciliated cells. These genes included FOXJ1, its upstream activator GMNC, and multiple FOXJ1-regulated genes that are associated with microtubules (MTs). Notably, FOXJ1 gene amplification was more frequent in taxane-exposed PC patients, and its overexpression conferred resistance to docetaxel both in vitro and in vivo. This resistance was associated with a decrease in docetaxel-mediated MT bundling, indicating that FOXJ1-regulated genes act at the level of tubulin to mitigate abnormal MT aggregation. Additionally, overexpression of an MT-associated FOXJ1-regulated gene (TPPP3) had similar effects. Conversely, FOXJ1 knockdown impaired basal MT function, enhanced taxane binding to MTs, and increased docetaxel sensitivity. Finally, analysis of data from the CHAARTED clinical trial showed that higher expression of FOXJ1 was predictive of decreased survival in PC patients treated with docetaxel. Together these findings highlight FOXJ1’s role in regulating MT dynamics in non-ciliated cells and that its increased expression mediates taxane resistance.

ORGANISM(S): Homo sapiens

PROVIDER: GSE276579 | GEO | 2025/09/01

REPOSITORIES: GEO

ACCESS DATA

Dataset's files

Source:

			Action	DRS
		Other

Items per page:

1 - 1 of 1

Similar Datasets

Project description:Prostate cancer (PC) typically depends on hormones for growth, with androgen deprivation therapy (ADT) serving as the primary treatment. However, many patients progress to a castration-resistant (CR) stage, where their tumor becomes unresponsive to ADT. Despite the common use of conventional chemotherapeutics like taxanes (docetaxel, cabazitaxel), the majority of patients experience recurrence. To uncover the mechanisms underlying the drug-resistant phenotype, we developed docetaxel-resistant CRPC cell lines, and through a drug library screen, we identified MLL-Menin and MLL-WDR5 inhibitors that overcome taxane resistance and significantly induced G2/M arrest and apoptosis. To determine the roles of individual proteins in the MLL complexes, we silenced several MLL partner proteins , and the absence of Menin and LEDGF particularly halted the growth of the resistant cells while showing no significant effect on parentals. Notably, parental cells with Menin silencing failed to develop resistance even after prolonged exposure, unlike their Menin-expressing counterparts, highlighting the critical role of Menin in the resistance process. Menin knockouts were analyzed through RNA-sequencing, and several gene sets, including E2F targets, G2/M checkpoints, and mTORC1 pathways, were found to be negatively regulated in taxane-resistant cells. The ablation of Menin led to a reduction in mTOR levels, and ChIP-qPCR analysis confirmed that Menin was enriched on the mTOR promoter. According to TCGA clinical data, the correlation between MEN1 and mTOR became stronger as the disease advanced to metastatic stages. Furthermore, the combination of the mTOR inhibitor Torin1 and docetaxel enhanced the sensitivity of our resistant cells. Menin deficiency reduced cell proliferation and key expression of cell cycle genes (Cyclin D1, CDK20). Rescue experiments reversed these effects, and Menin showed significant enrichment of the Cyclin D1 and CDK20 promoters. Finally, Menin loss impaired docetaxel resistant CRPC growth in our in vivo model. Our data demonstrate the essentiality of Menin for docetaxel resistance and suggest a combined approach targeting both Menin and mTOR to improve taxane therapy responses. Additionally, Menin regulates some key cell cycle genes to promote the G1/S transition, emphasizing its critical role in cell cycle regulation and the growth of taxane-resistant CRPC.

Project description:'Prostate cancer is the second cancer diagnosed among men worldwide. Beside approval of new therapies in the last five years, chemotherapeutic agents, docetaxel and cabazitaxel taxanes remain key treatments for metastatic castration resistant prostate cancers. However, primary and acquired resistance to taxanes still emerged in about half of patients. There is therefore an urgent need to discover and understand the taxane resistance mechanisms in order to identify new therapeutic targets. Indeed, targeted therapies that exploit the signaling pathways involved in prostate cancer are required to overcome chemoresistance and improve treatment outcomes. Molecular chaperones play a key role in the regulation of cellular homeostasis and the development of treatment resistance, and are promising therapeutic targets. Using high throughput siRNA functional screening based on a gene expression signature, we identified FKBP7, involved in acquired resistance to docetaxel and cabazitaxel. FKBP7 is a molecular chaperone that has not been studied in human so far. FKBP7 is overexpressed in prostate tumors and its expression is correlated with recurrence in patients who received docetaxel as neoadjuvant therapy. Moreover, FKBP7 is upregulated in taxane resistant prostate cancer cell lines and its expression sustains their growth in vitro and in a mice model of Docetaxel resistance. Using a high throughput proteomic approach, we identified the signaling pathway regulated by FKBP7 which is responsible for the survival of chemoresistant cells. Finally, we proposed a promising therapeutic strategy to overcome both docetaxel and cabazitaxel chemoresistance by targeting the downstream effector of FKBP7. Gene expression was profiled using a 4×44K Human Whole Genome (G4112F, id : 014850) expression array (Agilent Technologies, Santa Clara, Cal.) with a dual color dye-swap competitive hybridization procedure, according to the manufacturer''s instructions. Total RNA from untreated parental IGR-CaP1 cells was used as the RNA reference (NN1). Total RNA from IGR-CaP1 cells resistant to 5nM (NN2), 11.6nM (NN3), 25nM (NN4), 50nM (NN5), 100nM (NN6), and 200nM (NN7) of Docetaxel respectively, were used as samples. Two independent replicates of each samples (a and b) were used. Image analyses (quantification, normalization) were performed with Feature Extraction software (Agilent Technologies) and gene expression analysis was performed using Bioconductor.'

Dataset Information

FOXJ1 regulates microtubule dynamics in nonciliated cells and is a mediator of taxane resistance

Dataset's files

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets