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BRD9 inhibition as potential treatment option for testicular germ cell tumors

ABSTRACT: Testicular germ cell tumors (TGCT) are the predominant tumor in younger males. Usually, curation rates are quite high, but 15-20 % of patients with metastatic non-seminomas are resistant to standard cisplatin-based therapy. Interfering with the epigenetic landscape has already been shown to be effective in prostate cancer. BRD9 is an epigenetic reader which is part of the SWI-SNF chromatin-remodeling complex involved in regulation of gene expression. Alternative treatment options for therapy-resistant TGCT patients need to be investigated. BRD9 seems to be a promising target for analyzing the effect of BRD9 inhibition in TGCT cell lines. BRD9 expression was analyzed by meta-analysis of microarray data as well as by Western Blot and immunohistochemistry of tissue microarrays in TGCT cell lines and TGCT tissues. Viability was assessed by performing XTT-assay to determine the effect of BRD9 inhibition in TGCT cell lines. FACS analysis was used to display changes in cell cycle distribution as well as apoptosis. The impact on transcriptome level of BRD9 inhibition was analyzed by 3’mRNA-sequencing. BRD9 was heterogeneously expressed in TGCT cell lines and tissues. Nevertheless, inhibition of BRD9 led to strong decrease in viability. I-BRD9 induced apoptosis as well as cell cycle arrest in G1-phase. On transcriptome level, prominent downregulation of pluripotency markers (NANOG, PRMD14 and KLF4) and upregulation of genes involved in epithelium development were detected. I-BRD9 treatment of GCT cell lines reduced viability, induced apoptosis and cell cycle arrest while control cells remain mainly unaffected. Transcriptomic data indicate exit of pluripotency and differentiation towards the epithelial fate. In fact, loss of pluripotency and differentiation seems to be a common aspect of GCT reacting to drug application. The data implicate I-BRD9 as a possible treatment alternative for TGCTs.

ORGANISM(S): Homo sapiens

PROVIDER: GSE282367 | GEO | 2025/11/19

REPOSITORIES: GEO

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Project description:Malignant germ-cell-tumours (GCTs) are characterised by microRNA (miRNA/miR-) dysregulation, with universal over-expression of miR-371~373 and miR-302/367 clusters regardless of patient age, tumour site, or subtype (seminoma/yolk-sac-tumour/embryonal carcinoma). These miRNAs are released into the bloodstream, presumed within extracellular-vesicles (EVs) and represent promising biomarkers. Here, we comprehensively examined the role of EVs, and their miRNA cargo, on (fibroblast/endothelial/macrophage) cells representative of the testicular GCT (TGCT) tumour microenvironment (TME). Small RNA next-generation-sequencing was performed on 34 samples, comprising representative malignant GCT cell lines/EVs and controls (testis fibroblast [Hs1.Tes] cell-line/EVs and testis/ovary samples). TME cells received TGCT co-culture, TGCT-derived EVs, and a miRNA overexpression system (miR-371a-OE) to assess functional relevance. TGCT cells secreted EVs into culture media. MiR-371~373 and miR-302/367 cluster miRNAs were overexpressed in all TGCT cells/subtypes compared with control cells and were highly abundant in TGCT-derived EVs, with miR-371a-3p/miR-371a-5p the most abundant. TGCT co-culture resulted in increased levels of miRNAs from the miR-371~373 and miR-302/367 clusters in TME (fibroblast) cells. Next, fluorescent labelling demonstrated TGCT-derived EVs were internalised by all TME (fibroblast/endothelial/macrophage) cells. TME (fibroblast/endothelial) cell treatment with EVs derived from different TGCT subtypes resulted in increased miR-371~373 and miR-302/367 miRNA levels, and other generic (eg, miR-205-5p/miR-148-3p) and subtype-specific (seminoma, eg, miR-203a-3p; yolk-sac-tumour, eg, miR-375-3p) miRNAs. MiR-371a-OE in TME cells resulted in increased collagen contraction (fibroblasts) and angiogenesis (endothelial cells), via direct mRNA downregulation and alteration of relevant pathways. TGCT cells communicate with nontumour stromal TME cells through release of EVs enriched in oncogenic miRNAs, potentially contributing to tumour progression.

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BRD9 inhibition as potential treatment option for testicular germ cell tumors

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