|
既往研究已经证实，细胞核2C类蛋白磷酸酶PP2Cδ具有促癌作用，对于肿瘤形成起到重要作用。不过，PP2Cδ异常水平与乳腺癌生长的具体机制尚不明确。 2019年10月16日，美国科学促进会《科学》旗下《科学进展》在线发表同济大学附属东方医院、复旦大学附属肿瘤医院、美国斯坦福大学、查尔斯德鲁医科大学、洛杉矶加利福尼亚大学（通常被误译为加州大学洛杉矶分校）、北德克萨斯大学、加利福尼亚州立大学的研究报告，发现异常的PP2Cδ活性可以减少肿瘤抑制蛋白P53乙酰化及其转录活性，阻止乳腺癌细胞DNA损伤反应，并且抑制化疗药物多柔比星诱发的乳腺癌细胞凋亡。 根据机制分析，该研究发现乳腺癌易感基因编码的肿瘤抑制蛋白BRCA1通过与PP2Cδ和P53形成复合物，可以促进组蛋白乙酰转移酶P300诱发的P53乙酰化，而BRCA1第1423和1524位丝氨酸的磷酸化对于该调节过程必不可少。PP2Cδ通过肿瘤基因ATM编码的细胞分裂周期检查点激酶去磷酸化，可以抑制DNA损伤诱发的BRCA1磷酸化，从而抑制P300诱发的P53乙酰化。此外，PP2Cδ水平与组织学分级显著相关，并且与乳腺癌标本的BRCA1磷酸化和P53乙酰化水平成反比。最后，该研究新开发的PP2Cδ抑制剂C23，可以显著增强多柔比星对人类激素受体阳性乳腺癌细胞MCF-7异种移植裸鼠的抗癌作用。 因此，该研究数据表明，PP2Cδ可以通过抑制BRCA1功能，从而减少P53乙酰化及其转录活性，并且阻止乳腺癌细胞DNA损伤反应、化疗药物多柔比星诱发的乳腺癌细胞凋亡，故PP2Cδ有望成为提高乳腺癌化疗效果的新靶点。 Sci Adv. 2019 Oct 16;5(10):eaaw8417. PP2Cδ inhibits p300-mediated p53 acetylation via ATM/BRCA1 pathway to impede DNA damage response in breast cancer. Qun Li, Qiongyu Hao, Wei Cao, Jieqing Li, Ke Wu, Yahya Elshimali, Donghui Zhu, Qiao-hong Chen, Guanglin Chen, Jonathan R. Pollack, Jay Vadgama, Yong Wu. Shanghai East Hospital, Tongji University School of Medicine, Shanghai, China; Shanghai Cancer Center and Shanghai Medical College, Fudan University, Shanghai, China; Stanford University School of Medicine, Stanford, CA, USA; Charles Drew University of Medicine and Science, David Geffen UCLA School of Medicine, UCLA Jonsson Comprehensive Cancer Center, Los Angeles, CA, USA; University of North Texas, Denton, TX, USA; California State University, Fresno, Fresno, CA, USA. Although nuclear type 2C protein phosphatase (PP2Cδ) has been demonstrated to be pro-oncogenic with an important role in tumorigenesis, the underlying mechanisms that link aberrant PP2Cδ levels with cancer development remain elusive. Here, we found that aberrant PP2Cδ activity decreases p53 acetylation and its transcriptional activity and suppresses doxorubicin-induced cell apoptosis. Mechanistically, we show that BRCA1 facilitates p300-mediated p53 acetylation by complexing with these two proteins and that S1423/1524 phosphorylation is indispensable for this regulatory process. PP2Cδ, via dephosphorylation of ATM, suppresses DNA damage-induced BRCA1 phosphorylation, leading to inhibition of p300-mediated p53 acetylation. Furthermore, PP2Cδ levels correlate with histological grade and are inversely associated with BRCA1 phosphorylation and p53 acetylation in breast cancer specimens. C23, our newly developed PP2Cδ inhibitor, promotes the anticancer effect of doxorubicin in MCF-7 xenograft-bearing nude mice. Together, our data indicate that PP2Cδ impairs p53 acetylation and DNA damage response by compromising BRCA1 function. DOI: 10.1126/sciadv.aaw8417
|
|
|
