Plk1, upregulated by HIF-2, mediates metastasis and drug resistance of clear cell renal cell carcinoma
Open Access
- 5 February 2021
- journal article
- research article
- Published by Springer Science and Business Media LLC in Communications Biology
- Vol. 4 (1), 1-16
- https://doi.org/10.1038/s42003-021-01653-w
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.Keywords
Funding Information
- Fx Mora Foundation
- Fondation de France (fondation de France)
- Ligue Contre le Cancer ((Equipe Labellisée 2019)
- Fx Mora and Flavien foundation French Association for Cancer Research (ARC) the French National Institute for Cancer Research (INCA), the National Agency for Research
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