Physiological functions and roles in cancer of the proliferation marker Ki-67

ABSTRACT What do we know about Ki-67, apart from its usefulness as a cell proliferation biomarker in histopathology? Discovered in 1983, the protein and its regulation of expression and localisation throughout the cell cycle have been well characterised. However, its function and molecular mechanisms have received little attention and few answers. Although Ki-67 has long been thought to be required for cell proliferation, recent genetic studies have conclusively demonstrated that this is not the case, as loss of Ki-67 has little or no impact on cell proliferation. In contrast, Ki-67 is important for localising nucleolar material to the mitotic chromosome periphery and for structuring perinucleolar heterochromatin, and emerging data indicate that it also has critical roles in cancer development. However, its mechanisms of action have not yet been fully identified. Here, we review recent findings and propose the hypothesis that Ki-67 is involved in structuring cellular sub-compartments that assemble by liquid–liquid phase separation. At the heterochromatin boundary, this may control access of chromatin regulators, with knock-on effects on gene expression programmes. These changes allow adaptation of the cell to its environment, which, for cancer cells, is a hostile one. We discuss unresolved questions and possible avenues for future exploration.