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.
Highlights
Polo-like kinase 1 (Plk1) expression is inversely correlated with survival advantages in many cancers
We describe a molecular mechanism of the HIF2-Plk1-mediated clear cell renal cell carcinoma (ccRCC) metastasis and drug resistance
An in silico analysis revealed the presence of a consensus hypoxia response element (HRE) in the Plk[1] promoter (Supplementary Fig. 1a)
Summary
Polo-like kinase 1 (Plk1) expression is inversely correlated with survival advantages in many cancers. In ccRCC patients, high expression of Plk[1] was correlated to poor disease-free survival and overall survival. High Plk[1] expression conferred a resistant phenotype of ccRCC to targeted therapeutics such as sunitinib, in vitro, in vivo, and in metastatic ccRCC patients. Methylation status, mutation profile, cytogenetic anomalies, and immune cell infiltration, 4 subtypes of ccRCC patients (ccrcc1–4) have been classified[8,9,10,11]. These markers have prognostic and predictive values for guiding TKI-based therapy. We provide compelling experimental evidence to support our conclusions and relate our findings to clinical relevance
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