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Top2a complexes with Trim28 to orchestrate stemness of embryonic stem cells and tumorigenesis
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DOI：10.1038/s42003-026-10753-4.png)
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Abstract
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Type II topoisomerase α (Top2a) is crucial for maintaining the stemness of embryonic stem cells (ESCs) and is upregulated in various human cancers, yet the mechanisms underlying its cell type-specific functions remain elusive. Here, using an unbiased proteomic approach, we discovered that Trim28, along with subunits of various chromatin remodeling complexes and modifiers, interacts with Top2a on ESC chromatin. Specifically, Top2a directly interacts with Trim28 in mESCs but only weakly, if at all, in mouse embryonic fibroblasts (MEFs). Functionally, Trim28 cooperates with Top2a to maintain ESC status and enhance induced pluripotency. Genome-wide approaches revealed that Top2a and Trim28 co-activate a subset of genes encoding key metabolic enzymes involved in glycolysis in both ESCs and breast cancer cells. Mechanistically, high levels of Top2a fine-tune promoter bivalency by recruiting Trim28 to co-activated genes, while preventing its binding to co-repressed genes. Strikingly, targeting TOP2A in combination with TRIM28 in breast cancer cells leads to a superior anti-tumorigenic effect. Our findings thereby define a novel Top2a-Trim28 partnership for ESC-specific gene regulation, providing a rationale for the dual targeting of this axis in cancers with elevated TOP2A/TRIM28. A novel Top2a-Trim28 axis transcriptionally orchestrates glycolysis to control ESC stemness and tumorigenesis, supporting dual targeting in cancers with elevated TOP2A/TRIM28.
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