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Title: Elevation of adenylate energy charge by angiopoietin-like 4 enhances epithelial–mesenchymal transition by inducing 14-3-3γ expression
Authors: Teo, Ziqiang
Sng, Ming Keat
Chan, Jeremy Soon Kiat
Lim, Maegan Miang Kee
Li, Yinliang
Li, Luchun
Phua, Terri
Lee, J. Y. H.
Tan, Zhen Wei
Zhu, Pengcheng
Tan, Nguan Soon
Keywords: Cancer
Cell Biology
Issue Date: 2017
Source: Teo, Z., Sng, M. K., Chan, J. S. K., Lim, M. M. K., Li, Y., Li, L., et al. (2017). Elevation of adenylate energy charge by angiopoietin-like 4 enhances epithelial–mesenchymal transition by inducing 14-3-3γ expression. Oncogene, 36(46), 6408-6419.
Series/Report no.: Oncogene
Abstract: Metastatic cancer cells acquire energy-intensive processes including increased invasiveness and chemoresistance. However, how the energy demand is met and the molecular drivers that coordinate an increase in cellular metabolic activity to drive epithelial–mesenchymal transition (EMT), the first step of metastasis, remain unclear. Using different in vitro and in vivo EMT models with clinical patient’s samples, we showed that EMT is an energy-demanding process fueled by glucose metabolism-derived adenosine triphosphate (ATP). We identified angiopoietin-like 4 (ANGPTL4) as a key player that coordinates an increase in cellular energy flux crucial for EMT via an ANGPTL4/14-3-3γ signaling axis. This augmented cellular metabolic activity enhanced metastasis. ANGPTL4 knockdown suppresses an adenylate energy charge elevation, delaying EMT. Using an in vivo dual-inducible EMT model, we found that ANGPTL4 deficiency reduces cancer metastasis to the lung and liver. Unbiased kinase inhibitor screens and Ingenuity Pathway Analysis revealed that ANGPTL4 regulates the expression of 14-3-3γ adaptor protein via the phosphatidylinositol-3-kinase/AKT and mitogen-activated protein kinase signaling pathways that culminate to activation of transcription factors, CREB, cFOS and STAT3. Using a different mode of action, as compared with protein kinases, the ANGPTL4/14-3-3γ signaling axis consolidated cellular bioenergetics and stabilized critical EMT proteins to coordinate energy demand and enhanced EMT competency and metastasis, through interaction with specific phosphorylation signals on target proteins.
ISSN: 0950-9232
DOI: 10.1038/onc.2017.244
Rights: © 2017 The Author(s) (Nature Publishing Group). This work is licensed under a Creative Commons Attribution-NonCommercial-ShareAlike 4.0 International License. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in the credit line; if the material is not included under the Creative Commons license, users will need to obtain permission from the license holder to reproduce the material. To view a copy of this license, visit
Fulltext Permission: open
Fulltext Availability: With Fulltext
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