PR55α subunit of protein phosphatase 2A supports KRASG12D-driven tumorigenesis that requires YAP activation.

IF 7.3 1区 医学 Q1 BIOCHEMISTRY & MOLECULAR BIOLOGY
Christopher B Jenkins, Alison L Camero, Brendan T Graff, Lepakshe S V Madduri, Kelly A O'Connell, Ashley L Hein, Lynette M Smith, Charles A Enke, Jixin Dong, Michael A Hollingsworth, Keith R Johnson, Michel M Ouellette, Ying Yan
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引用次数: 0

Abstract

PP2A holoenzymes account nearly 50% of Ser/Thr phosphatase activities in human cells, yet their roles in oncogenesis remain largely unexplored. A PP2A holoenzyme consists of a catalytic subunit, a scaffold subunit, and a regulatory subunit. We previously reported that PR55α, a PP2A regulatory subunit, supports the tumorigenic and metastatic potential of pancreatic cancer cells, and this is associated with its role in promoting YAP activation, which is essential for tumorigenesis and progression in most solid tumors, including pancreatic cancer. However, the direct role of PR55α in tumorigenesis has not yet been assessed. Using telomerase-immortalized human pancreatic ductal cells (HPNE), this research reveals a mechanism in which PR55α/PP2A cooperates with oncogenic KRASG12D to drive cellular transformation and tumorigenesis in vivo. HPNE-transduced with PR55α and KRASG12D exhibited accelerated proliferation and migration, and anchorage-independent growth, hallmark features of malignant transformation. Biochemical studies demonstrated that PR55α-induced YAP activation was further enhanced by KRASG12D, primarily through the inhibition of the MST/LATS cascade. The essential role of YAP activation in HPNE transformation by PR55α and KRASG12D was confirmed by YAP inhibition. Finally, in vivo studies revealed that HPNE cells transformed by PR55α and KRASG12D were tumorigenic in mice. Collectively, these findings highlight the critical role of PR55α/PP2A in supporting KRAS-driven tumorigenesis, providing new insights into the mechanisms underlying pancreatic cancer progression.

蛋白磷酸酶2A的PR55α亚基支持krasg12d驱动的肿瘤发生,这需要YAP激活。
PP2A全酶占人类细胞中丝氨酸/苏氨酸磷酸酶活性的近50%,但其在肿瘤发生中的作用在很大程度上仍未被探索。PP2A全酶由催化亚基、支架亚基和调控亚基组成。我们之前报道了PP2A调控亚基PR55α支持胰腺癌细胞的致瘤性和转移潜力,这与其促进YAP激活的作用有关,而YAP激活对于大多数实体肿瘤(包括胰腺癌)的肿瘤发生和进展至关重要。然而,PR55α在肿瘤发生中的直接作用尚未被评估。本研究利用端粒酶永生化的人胰腺导管细胞(HPNE),揭示了PR55α/PP2A与致癌基因KRASG12D在体内协同驱动细胞转化和肿瘤发生的机制。PR55α和KRASG12D介导的hpne表现出加速的增殖和迁移,以及不依赖锚定的生长,这是恶性转化的标志特征。生化研究表明,KRASG12D主要通过抑制MST/LATS级联,进一步增强pr55 α-诱导的YAP活化。YAP激活在PR55α和KRASG12D转化HPNE中的重要作用被YAP抑制证实。最后,体内研究显示PR55α和KRASG12D转化的HPNE细胞在小鼠中具有致瘤性。总的来说,这些发现强调了PR55α/PP2A在支持kras驱动的肿瘤发生中的关键作用,为胰腺癌进展的机制提供了新的见解。
本文章由计算机程序翻译,如有差异,请以英文原文为准。
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来源期刊
Oncogene
Oncogene 医学-生化与分子生物学
CiteScore
15.30
自引率
1.20%
发文量
404
审稿时长
1 months
期刊介绍: Oncogene is dedicated to advancing our understanding of cancer processes through the publication of exceptional research. The journal seeks to disseminate work that challenges conventional theories and contributes to establishing new paradigms in the etio-pathogenesis, diagnosis, treatment, or prevention of cancers. Emphasis is placed on research shedding light on processes driving metastatic spread and providing crucial insights into cancer biology beyond existing knowledge. Areas covered include the cellular and molecular biology of cancer, resistance to cancer therapies, and the development of improved approaches to enhance survival. Oncogene spans the spectrum of cancer biology, from fundamental and theoretical work to translational, applied, and clinical research, including early and late Phase clinical trials, particularly those with biologic and translational endpoints.
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