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.
Communications biology. 2021 Feb 05*** epublish ***
Maeva Dufies, Annelies Verbiest, Lindsay S Cooley, Papa Diogop Ndiaye, Xingkang He, Nicolas Nottet, Wilfried Souleyreau, Anais Hagege, Stephanie Torrino, Julien Parola, Sandy Giuliano, Delphine Borchiellini, Renaud Schiappa, Baharia Mograbi, Jessica Zucman-Rossi, Karim Bensalah, Alain Ravaud, Patrick Auberger, Andréas Bikfalvi, Emmanuel Chamorey, Nathalie Rioux-Leclercq, Nathalie M Mazure, Benoit Beuselinck, Yihai Cao, Jean Christophe Bernhard, Damien Ambrosetti, Gilles Pagès
Centre Scientifique de Monaco, Biomedical Department, 8 quai Antoine Premier, 98 000, Monaco, Monaco. ., Department of General Medical Oncology, University Hospitals Leuven, 3000, Leuven, Belgium., University of Bordeaux, INSERM U1029, 33600, Pessac, France., LIA ROPSE, Laboratoire International Associé Université Côte d'Azur - Centre Scientifique de Monaco, Nice, France., Department of Microbiology, Tumor and Cell Biology, Karolinska Institutet, SE-171 77, Stockholm, Sweden., University Côte d'Azur, C3M, Inserm U1065, 06204, Nice, France., University Côte d'Azur, Institut de Pharmacologie Cellulaire et Moléculaire, CNRS UMR7275, 06560, Valbonne, France., Centre Antoine Lacassagne, 06189, Nice, France., University Côte d'Azur, Institute for Research on Cancer and Aging of Nice (IRCAN), CNRS UMR 7284; INSERM U1081, Centre Antoine Lacassagne, 06189, Nice, France., Inserm, UMR-1138, Génomique fonctionnelle des tumeurs solides, IUH, 75010, Paris, France., Centre Hospitalier Universitaire (CHU) de Pontchaillou Rennes, service d'urologie, 35000, Rennes, France., Centre Hospitalier Universitaire (CHU) de Bordeaux, service d'oncologie médicale, 33000, Bordeaux, France., Department of Pathology, University Hospital, 35000, Rennes, France., Centre Hospitalier Universitaire (CHU) de Bordeaux, service d'urologie, 33000, Bordeaux, France., University Côte d'Azur, Centre Hospitalier Universitaire (CHU) de Nice, Hôpital Pasteur, Central laboratory of Pathology, 06000, Nice, France., Centre Scientifique de Monaco, Biomedical Department, 8 quai Antoine Premier, 98 000, Monaco, Monaco. .
PubMed http://www.ncbi.nlm.nih.gov/pubmed/33547392