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

作者全名："Li, Yunzhe; Hu, Yunran; Yang, Lingling; Liu, Jingshu; Cui, Chenxi; Yang, Muyao; Zou, Dongling; Zhou, Lei; Zhou, Qi; Ge, Weihong; Lang, Tingyuan"

作者地址："[Li, Yunzhe; Yang, Muyao] Chongqing Univ, Coll Bioengn, Chongqing 400044, Peoples R China; [Hu, Yunran; Ge, Weihong] Nanjing Univ, Dept Pharm, Affiliated Drum Tower Hosp, Med Sch, Nanjing 210008, Jiangsu Provinc, Peoples R China; [Hu, Yunran; Ge, Weihong] China Pharmaceut Univ, Sch Basic Med & Clin Pharm, Nanjing 210009, Peoples R China; [Hu, Yunran; Ge, Weihong] Nanjing Univ, Affiliated Drum Tower Hosp, Med Sch, Nanjing 210008, Jiangsu, Peoples R China; [Yang, Lingling; Cui, Chenxi] Chongqing Univ, Sch Med, Chongqing 400044, Peoples R China; [Liu, Jingshu] Chongqing Med Univ, Obstet & Gynecol Dept, Affiliated Hosp 2, Chongqing 400010, Peoples R China; [Zou, Dongling; Zhou, Qi; Lang, Tingyuan] Chongqing Univ Canc Hosp, Dept Gynecol Oncol, Chongqing 400030, Peoples R China; [Zou, Dongling; Zhou, Qi; Lang, Tingyuan] Chongqing Canc Inst, Chongqing 400030, Peoples R China; [Zou, Dongling; Zhou, Qi; Lang, Tingyuan] Chongqing Canc Hosp, Chongqing 400030, Peoples R China; [Zhou, Lei] Hong Kong Polytech Univ, Sch Optometry, Dept Appl Biol & Chem Technol, 17W Hong Kong Sci Pk, Hong Kong, Peoples R China; [Zhou, Lei] Hong Kong Polytech Univ, Res Ctr SHARP Vis RCSV, Affiliated Hosp 1, Hong Kong 400042, Peoples R China"

通信作者："Ge, WH (通讯作者)，Nanjing Univ, Dept Pharm, Affiliated Drum Tower Hosp, Med Sch, Nanjing 210008, Jiangsu Provinc, Peoples R China.; Zhou, Q; Lang, TY (通讯作者)，Chongqing Univ Canc Hosp, Dept Gynecol Oncol, Chongqing 400030, Peoples R China.; Zhou, Q; Lang, TY (通讯作者)，Chongqing Canc Inst, Chongqing 400030, Peoples R China.; Zhou, Q; Lang, TY (通讯作者)，Chongqing Canc Hosp, Chongqing 400030, Peoples R China."

来源：BIOMEDICINE & PHARMACOTHERAPY

ESI学科分类：PHARMACOLOGY & TOXICOLOGY

WOS号：WOS:000943190600001

JCR分区：Q1

影响因子：7.5

年份：2023

卷号：160

期号：　

开始页：　

结束页：　

文献类型：Article

关键词：Luteolin; Ovarian cancer; Cancer stem cells; KDM4C; PPP2CA; YAP

摘要："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."

基金机构："Chongqing Science & Technology Commission [CSTB2022NSCQ-MSX1413, cstc2020jxjl130019, cstc2019jscx- msxmX0174]"

基金资助正文："We are grateful to professor Hongbin Ji from Shanghai Institutes for Biological Sciences for providing lentivirus plasmid. This work was supported by Chongqing Science & Technology Commission (CSTB2022NSCQ-MSX1413, cstc2020jxjl130019, cstc2019jscx-msxmX0174). We acknowledge the work of all our colleagues at Chongqing University, Singapore Eye Research Institute, Renji Hospital of Shanghai Jiao Tong University School of Medicine, and Shanghai Fourth People's Hospital of Tongji University School of Medicine."