Fisetin targets YB-1/RSK axis independent of its effect on ERK signaling: insights from in vitro and in vivo melanoma models

Sci Rep. 2018 Oct 24;8(1):15726. doi: 10.1038/s41598-018-33879-w.


The anti-proliferative activity of dietary flavonoid fisetin has been validated in various cancer models. Establishing its precise mechanism of action has proved somewhat challenging given the multiplicity of its targets. We demonstrated that YB-1 promotes epithelial-to-mesenchymal transition and its inhibition suppressed tumor cell proliferation and invasion. The p90 ribosomal S6 kinase (RSK), an important ERK effector, activates YB-1 to drive melanoma growth. We found that fisetin treatment of monolayer/3-D melanoma cultures resulted in YB-1 dephosphorylation and reduced transcript levels. In parallel, fisetin suppressed mesenchymal markers and matrix-metalloproteinases in melanoma cells. Data from cell-free/cell-based systems indicated that fisetin inhibited RSK activity through binding to the kinase. Affinity studies for RSK isoforms evaluated stronger interaction for RSK2 than RSK1. Competition assays performed to monitor binding responses revealed that YB-1 and RSK2 do not compete, rather binding of fisetin to RSK2 promotes its binding to YB-1. Fisetin suppressed YB-1/RSK signaling independent of its effect on ERK, and reduced MDR1 levels. Comparable efficacy of fisetin and vemurafenib for inhibiting melanoma growth was noted albeit through divergent modulation of ERK. Our studies provide insight into additional modes of regulation through which fisetin interferes with melanoma growth underscoring its potential therapeutic efficacy in disease progression.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Antineoplastic Agents / pharmacology
  • Cell Culture Techniques / methods
  • Cell Line, Tumor
  • Cell Proliferation / drug effects
  • Epithelial-Mesenchymal Transition / drug effects
  • Flavonoids / pharmacology*
  • Flavonols
  • Humans
  • MAP Kinase Signaling System
  • Melanoma / drug therapy*
  • Melanoma / pathology
  • Phosphorylation
  • Ribosomal Protein S6 Kinases, 90-kDa / metabolism*
  • Signal Transduction
  • Transcription, Genetic / drug effects
  • Y-Box-Binding Protein 1 / antagonists & inhibitors*
  • Y-Box-Binding Protein 1 / metabolism


  • Antineoplastic Agents
  • Flavonoids
  • Flavonols
  • Y-Box-Binding Protein 1
  • YBX1 protein, human
  • RPS6KA1 protein, human
  • Ribosomal Protein S6 Kinases, 90-kDa
  • fisetin