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

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 his-tone demethylation of PPP2CA promoter, inhibits PPP2CA transcription and PPP2CA-mediated YAP dephos-phorylation, 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.

Automated summary

In this study, it is found that luteolin, a natural flavonoid, directly binds to KDM4C and suppresses the stemness of ovarian cancer stem cells (OCSCs) by epigenetically inhibiting the PPP2CA/YAP axis. The maximal non-toxic dose of luteolin reduced the stemness properties of OCSCs, including sphere-forming capacity and the expression of OCSCs markers. Mechanistically, luteolin blocked KDM4C-induced histone demethylation of the PPP2CA promoter, leading to the inhibition of PPP2CA transcription and YAP dephosphorylation, thus attenuating YAP activity and the stemness of OCSCs.