Journal Article

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

Borchiellini Delphine, Schiappa Renaud, Ambrosetti Damien, Dufies Maeva, Zucman-Rossi, Jessica, Auberger, Patrick, Giuliano, Sandy, Chamorey Emmanuel, Ravaud Alain, Parola Julien, Bensalah Karim, Bikfalvi Andréas, Pagès Gilles, Beuselinck Benoit, Torrino Stephanie, Hagege Anais, Christophe, Bernhard Jean, Rioux-Leclercq Nathalie, Souleyreau Wilfried, Mograbi Baharia, Ndiaye, Papa Diogop, Cao Yihai, Cooley, Lindsay S, Mazure, Nathalie M, Nottet Nicolas, Verbiest Annelies, He Xingkang

2021

Overview

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.Dufies et al. find high Plk1 expression levels in aggressive clear cell renal cell carcinoma and discover that Plk1 is transcriptionally upregulated in a manner dependent on HIF-2. They also find that high Plk1 expression is correlated to a poor prognosis and resistance to tyrosine kinase inhibitor against VEGF receptor, suggesting a critical role for hypoxia/HIF-2-induced Plk1 in disease progression.

• Publisher: Nature Publishing Group
• Subject: Biology / Clear cell-type renal cell carcinoma / Drug resistance / Enzyme inhibitors / Hypoxia / Kidney cancer / Medical prognosis / Metastases / Metastasis / Molecular modelling / Phenotypes / Polo-like kinase / Polo-like kinase 1 / Protein-tyrosine kinase / Transcription / Vascular endothelial growth factor