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Plk1, upregulated by HIF-2, mediates metastasis and drug resistance of clear cell renal cell carcinoma

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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

Edité par CCSD ; Nature Publishing Group -

International audience. 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. Lossof-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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