Luteolin directly binds to KDM4C and attenuates ovarian cancer stemness via epigenetic suppression of PPP2CA/YAP axis

Yunzhe Li, Yunran Hu, Lingling Yang, Jingshu Liu, Chenxi Cui, Muyao Yang, Dongling Zou, Lei Zhou, Qi Zhou (Corresponding Author), Weihong Ge (Corresponding Author), Tingyuan Lang (Corresponding Author)

Research output: Journal article publicationJournal articleAcademic researchpeer-review

Abstract

Long-term use of low-toxic natural products holds the promise for eradicating cancer stem cells. In this study, we report that luteolin, a natural flavonoid, attenuates the stemness of ovarian cancer stem cells (OCSCs) by directly binding to KDM4C and epigenetic suppression of PPP2CA/YAP axis. Ovarian cancer stem like cells (OCSLCs) isolated by suspension culture and CD133 + ALDH+ cell sorting was employed as OCSCs model. The maximal non-toxic dose of luteolin suppressed stemness properties, including sphere-forming capacity, the expression of OCSCs markers, sphere-initiating and tumor-initiating capacities, as well as the percentage of CD133 + ALDH+ cells of OCSLCs. Mechanistic study showed that luteolin directly binds to KDM4C, blocks KDM4C-induced histone demethylation of PPP2CA promoter, inhibits PPP2CA transcription and PPP2CA-mediated YAP dephosphorylation, thereby attenuating YAP activity and the stemness of OCSLCs. Furthermore, luteolin sensitized OCSLCs to traditional chemotherapeutic drugs in vitro and in vivo. In summary, our work revealed the direct target of luteolin and the underlying mechanism of the inhibitory effect of luteolin on the stemness of OCSCs. This finding thus suggests a novel therapeutic strategy for eradicating human OCSCs driven by KDM4C.

Original languageEnglish
Article number114350
JournalBiomedicine and Pharmacotherapy
Volume160
DOIs
Publication statusPublished - 16 Feb 2023

Keywords

  • Cancer stem cells
  • KDM4C
  • Luteolin
  • Ovarian cancer
  • PPP2CA
  • YAP

ASJC Scopus subject areas

  • Pharmacology

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