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

• DOI: 10.1038/s42003-021-01653-w
• Publication Date: 2021-02-05T11:38:05Z
• Authors: 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 Borchiel...; Renaud Schiappa; Baharia Mograbi; Jessica Zucman-Rossi; Karim Bensalah; Alain Ravaud; Patrick Auberger; Andréas Bikfalvi; Emmanuel Chamorey; Nathalie Rioux-Le...; Nathalie M. Mazure; Benoit Beuselinck; Yihai Cao; Jean Christophe B...; Damien Ambrosetti; Gilles Pagès
• Keywords: Life Sciences & Biomedicine - Other Topics; 0301 basic medicine; Embryo, Nonmammalian; QH301-705.5; [SDV]Life Sciences [q-bio]; Mice, Nude; Cell Cycle Proteins; Protein Serine-Threonine Kinases; Article; Cohort Studies; Mice; 03 medical and health sciences; Cell Line, Tumor; Proto-Oncogene Proteins; Antineoplastic Combined Chemotherapy Protocols; Animals; Humans; Biology (General); Neoplasm Metastasis; Biology; Carcinoma, Renal Cell; Zebrafish; Cell Proliferation; Science & Technology; Kidney Neoplasms; Up-Regulation; 3. Good health; [SDV] Life Sciences [q-bio]; Multidisciplinary Sciences; Gene Expression Regulation, Neoplastic; Drug Resistance, Neoplasm; Science & Technology - Other Topics; Female; Life Sciences & Biomedicine

AbstractPolo-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.