Ki-67 regulates global gene expression and promotes sequential stages of carcinogenesis
Menée à l'aide de modèles murins, cette étude met en évidence un mécanisme par lequel la protéine nucléaire ki-67, en réduisant l'expression de certains gènes, favorise différentes phases de la carcinogenèse
Ki-67 is a nuclear protein present in all proliferating vertebrate cells and is widely used as a marker in clinical cancer histopathology. However, its cellular functions have remained largely mysterious, and whether it plays any roles in cancer was unknown. In this work, we show genetically that Ki-67 is not required for cell proliferation in tumors, but it is required for all stages of carcinogenesis. The effects on cell transformation, tumor growth, metastasis, and drug sensitivity correlate with genome-scale changes in gene expression that modify cellular programs implicated in cancer. Thus, Ki-67 expression is advantageous for cancer cells, but it comes with an Achilles’ heel: it makes them more visible to the immune system.Ki-67 is a nuclear protein that is expressed in all proliferating vertebrate cells. Here, we demonstrate that, although Ki-67 is not required for cell proliferation, its genetic ablation inhibits each step of tumor initiation, growth, and metastasis. Mice lacking Ki-67 are resistant to chemical or genetic induction of intestinal tumorigenesis. In established cancer cells, Ki-67 knockout causes global transcriptome remodeling that alters the epithelial–mesenchymal balance and suppresses stem cell characteristics. When grafted into mice, tumor growth is slowed, and metastasis is abrogated, despite normal cell proliferation rates. Yet, Ki-67 loss also down-regulates major histocompatibility complex class I antigen presentation and, in the 4T1 syngeneic model of mammary carcinoma, leads to an immune-suppressive environment that prevents the early phase of tumor regression. Finally, genes involved in xenobiotic metabolism are down-regulated, and cells are sensitized to various drug classes. Our results suggest that Ki-67 enables transcriptional programs required for cellular adaptation to the environment. This facilitates multiple steps of carcinogenesis and drug resistance, yet may render cancer cells more susceptible to antitumor immune responses.All RNA-Seq and ChIP-Seq raw data have been deposited in the Gene Expression Omnibus as a SuperSeries on December 13, 2020 (accession no. GSE163114).