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研究发现抑制STRN3可恢复胃癌细胞中Hippo的抑癌功能
作者:小柯机器人 发布时间:2020/6/28 11:56:23

复旦大学周兆才、焦石课题组近日取得一项新成果。经过不懈努力,他们发现选择性抑制PP2A磷酸酶的STRN3亚基可恢复胃癌细胞中Hippo激酶的肿瘤抑制活性。2020年6月25日,国际学术期刊《癌细胞》在线发表了这一成果。

研究人员发现STRN3是蛋白磷酸酶2A(PP2A)的必需调节亚基,其招募MST1 / 2并促其去磷酸化,这导致YAP激活。研究还发现胃癌中STRN3的上调与YAP激活和不良预后有关。基于对这种机制的理解并借助结构指导的药物化学,研究人员设计了一种高度选择性的肽抑制剂,STRN3衍生的Hippo激活肽或SHAP,它可以破坏STRN3-PP2Aa间的相互作用并重新激活Hippo的抑癌活性,抑制YAP激活并在体内具有抗肿瘤作用。

据介绍,通常在癌症中观察到Hippo抑癌活性的丧失和YAP的过度活化。Hippo激酶MST1 / 2的失活突变并不常见,目前尚不清楚在肿瘤发生过程中它们活性的关闭机制。

附:英文原文

Title: Selective Inhibition of STRN3-Containing PP2A Phosphatase Restores Hippo Tumor-Suppressor Activity in Gastric Cancer

Author: Yang Tang, Gemin Fang, Fenghua Guo, Hui Zhang, Xiaoxu Chen, Liwei An, Min Chen, Li Zhou, Wenjia Wang, Tiantian Ye, Lei Zhou, Pingping Nie, Haijun Yu, Moubin Lin, Yun Zhao, Xinhua Lin, Zengqiang Yuan, Shi Jiao, Zhaocai Zhou

Issue&Volume: 2020-06-25

Abstract: Loss of Hippo tumor-suppressor activity and hyperactivation of YAP are commonly observedin cancers. Inactivating mutations of Hippo kinases MST1/2 are uncommon, and it remainsunclear how their activity is turned off during tumorigenesis. We identified STRN3as an essential regulatory subunit of protein phosphatase 2A (PP2A) that recruitsMST1/2 and promotes its dephosphorylation, which results in YAP activation. We alsoidentified STRN3 upregulation in gastric cancer correlated with YAP activation andpoor prognosis. Based on this mechanistic understanding and aided by structure-guidedmedicinal chemistry, we developed a highly selective peptide inhibitor, STRN3-derivedHippo-activating peptide, or SHAP, which disrupts the STRN3-PP2Aa interaction andreactivates the Hippo tumor suppressor, inhibits YAP activation, and has antitumoreffects in vivo.

DOI: 10.1016/j.ccell.2020.05.019

Source: https://www.cell.com/cancer-cell/fulltext/S1535-6108(20)30269-5

期刊信息

Cancer Cell:《癌细胞》,创刊于2002年。隶属于细胞出版社,最新IF:23.916
官方网址:https://www.cell.com/cancer-cell/home
投稿链接:https://www.editorialmanager.com/cancer-cell/default.aspx