OCT4 directly regulates stemness and extracellular matrix-related genes in human germ cell tumours
Bomin Song1, Dong Keon Kim2, Jihoon Shin3
1Research Institute, National Cancer Center, Goyang, 10408, Republic of Korea; Department of Life Sciences, Ewha Womans University, Seoul, 03760, Republic of Korea.
Abstract:
Germ cell tumours (GCTs) are one of the most threatening malignancies in young men and women. Although several reports have suggested the importance of OCT4 in human GCTs, its role has not been clearly investigated on a molecular level. In this study, we revealed GCT-specific direct transcriptional target genes of OCT4. Conditional knockdown of OCT4 in GCT cell lines reduced cell proliferation by affecting both cell cycle and death. Knockdown of OCT4 also reduced stemness of GCTs, as assessed by the expression of other stemness factors, alkaline phosphatase staining, and tumour sphere formation ability. Analysis of whole mRNA expression patterns among GCT cells harbouring endogenous, depleted, and rescued OCT4 revealed 1133 OCT4 target genes in GCT. Combined analysis of both the chromatin binding signature of OCT4 and the genes whose expression levels were changed by OCT4 revealed 258 direct target genes of OCT4 in GCTs. In a similar way, 594 direct target genes in normal embryonic stem cells (ESCs) were identified. Among these two sets of OCT4 direct target genes, 38 genes were common between GCTs and ESCs, most of which were related to regulation of pluripotency, and 220 genes were specific to GCTs, most of which were related to focal adhesion and extracellular matrix organisation. These results provide a molecular basis for how OCT4 regulates GCT stemness and will aid our understanding of the role of OCT4 in other cancers.
Insights
Octamer-binding transcription factor 4 (OCT4) drives germ cell tumor (GCT) stemness by regulating specific genes. Targeting OCT4 impacts GCT cell proliferation, cell cycle, and cell death, offering new therapeutic insights.
Area of Science:
- Oncology
- Molecular Biology
- Genetics
Background:
- Germ cell tumors (GCTs) are aggressive malignancies affecting young individuals.
- The role of Octamer-binding transcription factor 4 (OCT4) in GCTs is significant but not fully understood at a molecular level.
Purpose of the Study:
- To identify OCT4-specific direct transcriptional target genes in GCTs.
- To elucidate the molecular mechanisms by which OCT4 regulates GCT stemness and proliferation.
Main Methods:
- Conditional knockdown of OCT4 in GCT cell lines.
- Analysis of whole mRNA expression patterns and chromatin binding signatures.
- Assessment of stemness markers including alkaline phosphatase staining and tumor sphere formation.
Main Results:
- OCT4 knockdown reduced GCT cell proliferation by affecting cell cycle and apoptosis.
- Identified 258 direct OCT4 target genes in GCTs, with 220 specific to GCTs and involved in focal adhesion and extracellular matrix organization.
- 38 common direct target genes between GCTs and embryonic stem cells (ESCs) were related to pluripotency regulation.
Conclusions:
- OCT4 plays a crucial role in maintaining GCT stemness and proliferation through specific transcriptional targets.
- Findings provide a molecular basis for OCT4's function in GCTs and suggest potential therapeutic strategies targeting OCT4 in various cancers.
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