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

Commun Biol. 2021 Feb 5;4(1):166. doi: 10.1038/s42003-021-01653-w.


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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Antineoplastic Combined Chemotherapy Protocols / therapeutic use
  • Carcinoma, Renal Cell* / drug therapy
  • Carcinoma, Renal Cell* / genetics
  • Carcinoma, Renal Cell* / pathology
  • Cell Cycle Proteins / genetics
  • Cell Cycle Proteins / physiology*
  • Cell Line, Tumor
  • Cell Proliferation / genetics
  • Cohort Studies
  • Drug Resistance, Neoplasm / genetics*
  • Embryo, Nonmammalian
  • Female
  • Gene Expression Regulation, Neoplastic
  • Humans
  • Kidney Neoplasms* / drug therapy
  • Kidney Neoplasms* / genetics
  • Kidney Neoplasms* / pathology
  • Mice
  • Mice, Nude
  • Neoplasm Metastasis
  • Protein Serine-Threonine Kinases / genetics
  • Protein Serine-Threonine Kinases / physiology*
  • Proto-Oncogene Proteins / genetics
  • Proto-Oncogene Proteins / physiology*
  • Up-Regulation / genetics
  • Zebrafish


  • Cell Cycle Proteins
  • Proto-Oncogene Proteins
  • Protein Serine-Threonine Kinases
  • polo-like kinase 1