The YAP1-MAML2 fusion drives tumorigenesis and sustains tumor growth

被引:0
|
作者
Ni, Wei [1 ,2 ,3 ]
Yu, Mu [1 ,2 ]
Yang, Rongqiang [1 ,2 ]
Li, Jennifer W. [4 ]
Zhou, Xin [1 ,2 ]
Calbay, Ozlem [2 ,5 ]
Pi, Liya [6 ]
Lu, Jianrong [2 ,7 ]
Huang, Shuang [2 ,5 ]
Wu, Lizi [1 ,2 ,3 ]
机构
[1] Univ Florida, Dept Mol Genet & Microbiol, Gainesville, FL 32610 USA
[2] Univ Florida, UF Hlth Canc Ctr, Gainesville, FL 32610 USA
[3] Univ Florida, UF Inst Genet, Gainesville, FL 32610 USA
[4] Brown Univ, Dept Med, Providence, RI 02912 USA
[5] Univ Florida, Dept Anat & Cell Biol, Gainesville, FL 32610 USA
[6] Tulane Univ, Sch Med, Dept Pathol & Lab Med, New Orleans, LA 70112 USA
[7] Univ Florida, Dept Biochem & Mol Biol, Gainesville, FL 32610 USA
来源
MOLECULAR THERAPY ONCOLOGY | 2024年 / 32卷 / 04期
基金
美国国家卫生研究院;
关键词
TRANSCRIPTIONAL COACTIVATORS; YAP; GENE;
D O I
10.1016/j.omton.2024.200900
中图分类号
R73 [肿瘤学];
学科分类号
100214 ;
摘要
The Yes!-associated transcriptional regulator-mastermind-like transcriptional co-activator 2 (YAP!-MAML2 [YM]) fusion protein arises from an intrachromosomal inversion and is implicated in various cancers. However, the oncogenic role of the endogenous YM fusion protein remained undefined. In this study, we employed YM-positive ES-2 ovarian cancer cells as a model to explore the roles of the YM fusion in cancer initiation and maintenance. The YM fusion protein localizes to nuclear speckles and contains bifunctional domains: the YAP! N-terminal domain interacts with transcriptional enhanced associate domain (TEAD) transcription factors, while the MAML2 C-terminal domain activates YAP!/TEAD-driven transcription. YM exhibited transforming activity, as shown by its ability to induce focus formation in immortalized epithelial cells. YM depletion reduced cancer cell proliferation and survival both in vitro and in xenograft tumor models. This effect was correlated with a downregulation of YAP!/TEADdriven genes essential for cellular proliferation and survival, as revealed by transcriptomic analysis. Importantly, YM-positive cancer cells were sensitive to YAP!/TEAD-targeted pharmacologic inhibition. Collectively, these fi ndings establish the YM fusion as a critical driver of oncogenesis and a promising therapeutic target for cancers harboring the YM fusion.
引用
收藏
页数:12
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