Ki-67 supports global gene expression programmes driving tumourigenesis

Ki-67 is a nuclear protein universally expressed in proliferating vertebrate cells (1), a characteristic that underlies its widespread use as a cancer biomarker. It organises heterochromatin (2,3) and the mitotic chromosome periphery (2,4–6), but it is dispensable for cell proliferation in vivo2. It thus remains unclear whether Ki-67 confers any advantages to cancer cells. Here, using mouse models of breast and intestinal cancer, we show that Ki-67 ensures gene expression programmes required for both carcinogenesis and tumour immunogenicity. We find that germline disruption of Ki-67 protects mice against intestinal tumourigenesis, while in mammary carcinoma cells, ablation of Ki-67 slows tumour growth and inhibits metastasis, despite the failure of cells lacking Ki-67 to induce an effective anti-tumour immune response. Mechanistically, Ki-67 loss leads to widespread deregulation of gene expression, including genes involved in the epithelial-mesenchymal transition (EMT), immune responses and drug metabolism. This results in loss of mesenchymal and stem cell characteristics, downregulation of MHC class I expression and sensitisation to various drug classes. Our results suggest that, by structuring chromatin to allow global transcriptome changes, Ki-67 allows cancer cells to adapt to their environment. This is required for all stages of tumourigenesis and drug resistance, but, by maintaining tumour immunogenicity, it also confers a targetable vulnerability on cancer cells.