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Dufies, Maeva; Verbiest, Annelies; Cooley, Lindsay S; Ndiaye, Papa Diogop; He, Xingkang; Nottet, Nicolas; Souleyreau, Wilfried; Hagege, Anais; Torrino, Stephanie; Parola, Julien; Giuliano, Sandy; Borchiellini, Delphine; Schiappa, Renaud; Mograbi, Baharia; Zucman-Rossi, Jessica; Bensalah, Karim; Ravaud, Alain; Auberger, Patrick; Bikfalvi, Andréas; Chamorey, Emmanuel; Rioux-Leclercq, Nathalie; Mazure, Nathalie M; Beuselinck, Benoit; Cao, Yihai; Bernhard, Jean Christophe; Ambrosetti, Damien; Pagès, Gilles
Communications biology, 02/2021, Volume: 4, Issue: 1Journal Article
Polo-like kinase 1 (Plk1) expression is inversely correlated with survival advantages in many cancers. However, molecular mechanisms that underlie Plk1 expression are poorly understood. Here, we uncover a hypoxia-regulated mechanism of Plk1-mediated cancer metastasis and drug resistance. We demonstrated that a HIF-2-dependent regulatory pathway drives Plk1 expression in clear cell renal cell carcinoma (ccRCC). Mechanistically, HIF-2 transcriptionally targets the hypoxia response element of the Plk1 promoter. In ccRCC patients, high expression of Plk1 was correlated to poor disease-free survival and overall survival. Loss-of-function of Plk1 in vivo markedly attenuated ccRCC growth and metastasis. High Plk1 expression conferred a resistant phenotype of ccRCC to targeted therapeutics such as sunitinib, in vitro, in vivo, and in metastatic ccRCC patients. Importantly, high Plk1 expression was defined in a subpopulation of ccRCC patients that are refractory to current therapies. Hence, we propose a therapeutic paradigm for improving outcomes of ccRCC patients.
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