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.
Authors
Lian Zhou, Su Zhang, Lingli Wang, Xueqin Liu, Xuyang Yang, Lei Qiu, Ying Zhou, Qing Huang, Yang Meng, Xue Lei, Linda Wen, Junhong Han
This file is in Adobe Acrobat (PDF) format. If you have not installed and configured the Adobe Acrobat Reader on your system.
Having trouble reading a PDF?
PDFs are designed to be printed out and read, but if you prefer to read them online, you may find it easier if you increase the view size to 125%.
Having trouble saving a PDF?
Many versions of the free Acrobat Reader do not allow Save. You must instead save the PDF from the JCI Online page you downloaded it from. PC users: Right-click on the Download link and choose the option that says something like "Save Link As...". Mac users should hold the mouse button down on the link to get these same options.
Having trouble printing a PDF?
- Try printing one page at a time or to a newer printer.
- Try saving the file to disk before printing rather than opening it "on the fly." This requires that you configure your browser to "Save" rather than "Launch Application" for the file type "application/pdf", and can usually be done in the "Helper Applications" options.
- Make sure you are using the latest version of Adobe's Acrobat Reader.
