Plk1, upregulated by HIF-2, mediates metastasis and drug resistance of clear cell renal cell carcinoma - Université Paris Cité Accéder directement au contenu
Article Dans Une Revue Communications Biology Année : 2021

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

Alain Ravaud
Yihai Cao

Résumé

Abstract 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.

Dates et versions

hal-03429104 , version 1 (15-11-2021)

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Citer

Maeva Dufies, Annelies Verbiest, Lindsay Cooley, Papa Diogop Ndiaye, Xingkang He, et al.. Plk1, upregulated by HIF-2, mediates metastasis and drug resistance of clear cell renal cell carcinoma. Communications Biology, 2021, 4 (1), ⟨10.1038/s42003-021-01653-w⟩. ⟨hal-03429104⟩
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