PCYT2 inhibits epithelial-mesenchymal transition in colorectal cancer by elevating YAP1 phosphorylation.

IF 6.3 1区 医学 Q1 MEDICINE, RESEARCH & EXPERIMENTAL
Lian Zhou, Su Zhang, Lingli Wang, Xueqin Liu, Xuyang Yang, Lei Qiu, Ying Zhou, Qing Huang, Yang Meng, Xue Lei, Linda Wen, Junhong Han
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引用次数: 0

Abstract

Metabolic reprogramming is a common feature in tumor progression and metastasis. Like proteins, lipids can transduce signals through lipid-protein interactions. During tumor initiation and metastasis, dysregulation of the Hippo pathway plays a critical role. Specifically, the inhibition of YAP1 phosphorylation leads to the relocation of YAP1 to the nucleus to activate transcription of genes involved in metastasis. Although recent studies reveal the involvement of phosphatidylethanolamine (PE) synthesis enzyme phosphoethanolamine cytidylyltransferase 2 (PCYT2) in tumor chemoresistance, the effect of PCYT2 on tumor metastasis remains elusive. Here, we show that PCYT2 was significantly downregulated in metastatic colorectal cancer (CRC) and acted as a tumor metastasis suppressor. Mechanistically, PCYT2 increased the interaction between PEBP1 and YAP1-phosphatase PPP2R1A, thus disrupting PPP2R1A-YAP1 association. As a result, phosphorylated YAP1 levels were increased, leading to YAP1 degradation through the ubiquitin protease pathway. YAP1 reduction in the nucleus repressed the transcription of ZEB1 and SNAIL2, eventually resulting in metastasis suppression. Our work provides insight into the role of PE synthesis in regulating metastasis and presents PCYT2 as a potential therapeutic target for CRC.

PCYT2 通过提高 YAP1 磷酸化抑制结直肠癌上皮细胞向间质转化。
代谢重编程是肿瘤进展和转移的一个共同特征。与蛋白质一样,脂质也能通过脂质与蛋白质的相互作用传递信号。在肿瘤发生和转移过程中,Hippo 通路的失调起着至关重要的作用。具体来说,抑制 YAP1 磷酸化会导致 YAP1 转位至细胞核,从而激活转移相关基因的转录。尽管最近的研究揭示了磷脂酰乙醇胺(PE)合成酶磷脂酰乙醇胺胞苷键转移酶2(PCYT2)参与了肿瘤化疗耐药性的作用,但PCYT2对肿瘤转移的影响仍然难以捉摸。在这里,我们发现 PCYT2 在转移性结直肠癌(CRC)中显著下调,并作为肿瘤转移抑制因子发挥作用。从机理上讲,PCYT2增加了PEBP1和YAP1-磷酸酶PPP2R1A之间的相互作用,从而破坏了PPP2R1A-YAP1的关联。因此,磷酸化-YAP1 水平增加,导致 YAP1 通过泛素蛋白酶途径降解。YAP1在细胞核中的减少抑制了ZEB1和Snail2的转录,最终导致转移抑制。我们的研究深入揭示了PE合成在调控转移中的作用,并将PCYT2作为CRC的潜在治疗靶点。
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来源期刊
JCI insight
JCI insight Medicine-General Medicine
CiteScore
13.70
自引率
1.20%
发文量
543
审稿时长
6 weeks
期刊介绍: JCI Insight is a Gold Open Access journal with a 2022 Impact Factor of 8.0. It publishes high-quality studies in various biomedical specialties, such as autoimmunity, gastroenterology, immunology, metabolism, nephrology, neuroscience, oncology, pulmonology, and vascular biology. The journal focuses on clinically relevant basic and translational research that contributes to the understanding of disease biology and treatment. JCI Insight is self-published by the American Society for Clinical Investigation (ASCI), a nonprofit honor organization of physician-scientists founded in 1908, and it helps fulfill the ASCI's mission to advance medical science through the publication of clinically relevant research reports.
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