國家衛生研究院 NHRI:Item 3990099045/12968
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    题名: Targeting the histone demethylase PHF8-mediated PKCalpha-Src-PTEN axis in HER2-negative gastric cancer
    其它题名: Targeting the histone demethylase PHF8-mediated PKCα-Src-PTEN axis in HER2-negative gastric cancer
    作者: Tseng, LL;Cheng, HH;Yeh, TS;Huang, SC;Syu, YY;Chuu, CP;Yuh, CH;Kung, HJ;Wang, WC
    贡献者: Institute of Cellular and Systems Medicine;Institute of Molecular and Genomic Medicine
    摘要: Targeted treatments for advanced gastric cancer (GC) are needed, particularly for HER2-negative GC, which represents the majority of cases (80 to 88%). In this study, in silico analyses of the lysine histone demethylases (KDMs) involved in diverse biological processes and diseases revealed that PHD finger protein 8 (PHF8, KDM7B) was significantly associated with poor clinical outcome in HER2-negative GC. The depletion of PHF8 significantly reduced cancer progression in GC cells and in mouse xenografts. PHF8 regulated genes involved in cell migration/motility based on a microarray analysis. Of note, PHF8 interacted with c-Jun on the promoter of PRKCA which encodes PKCα. The depletion of PHF8 or PKCα greatly up-regulated PTEN expression, which could be rescued by ectopic expression of a PKCα expression vector or an active Src. These suggest that PTEN destabilization occurs mainly via the PKCα-Src axis. GC cells treated with midostaurin or bosutinib significantly suppressed migration in vitro and in zebrafish models. Immunohistochemical analyses of PHF8, PKCα, and PTEN showed a positive correlation between PHF8 and PKCα but negative correlations between PHF8 and PTEN and between PKCα and PTEN. Moreover, high PHF8-PKCα expression was significantly correlated with worse prognosis. Together, our results suggest that the PKCα-Src-PTEN pathway regulated by PHF8/c-Jun is a potential prognostic/therapeutic target in HER2-negative advanced GC.
    日期: 2020-09-21
    關聯: Proceedings of the National Academy of Sciences of the United States of America. 2020 Sep 21;117(40):24859-24866.
    Link to: http://dx.doi.org/10.1073/pnas.1919766117
    JIF/Ranking 2023: http://gateway.webofknowledge.com/gateway/Gateway.cgi?GWVersion=2&SrcAuth=NHRI&SrcApp=NHRI_IR&KeyISSN=0027-8424&DestApp=IC2JCR
    Cited Times(WOS): https://www.webofscience.com/wos/woscc/full-record/WOS:000579014500012
    Cited Times(Scopus): https://www.scopus.com/inward/record.url?partnerID=HzOxMe3b&scp=85092681845
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