Format

Send to

Choose Destination
Oncogene. 2015 Jul 23;34(30):3908-16. doi: 10.1038/onc.2014.321. Epub 2014 Oct 6.

Metabolic reprogramming during TGFβ1-induced epithelial-to-mesenchymal transition.

Author information

1
Children's Medical Center Research Institute, Dallas, TX, USA.
2
Department of Pharmacology and Radiation Oncology, UT Southwestern Medical Center, Dallas, TX, USA.
3
1] Department of Pharmacology and Radiation Oncology, UT Southwestern Medical Center, Dallas, TX, USA [2] Department of Pathology, UT Southwestern Medical Center, Dallas, TX, USA.
4
Department of Internal Medicine, UT Southwestern Medical Center, Dallas, TX, USA.
5
1] Department of Pathology, UT Southwestern Medical Center, Dallas, TX, USA [2] Center for Molecular Medicine, Jichi Medical University, Tochigi, Japan.

Abstract

Metastatic progression, including extravasation and micrometastatic outgrowth, is the main cause of cancer patient death. Recent studies suggest that cancer cells reprogram their metabolism to support increased proliferation through increased glycolysis and biosynthetic activities, including lipogenesis pathways. However, metabolic changes during metastatic progression, including alterations in regulatory gene expression, remain undefined. We show that transforming growth factor beta 1 (TGFβ1)-induced epithelial-to-mesenchymal transition (EMT) is accompanied by coordinately reduced enzyme expression required to convert glucose into fatty acids, and concomitant enhanced respiration. Overexpressed Snail1, a transcription factor mediating TGFβ1-induced EMT, was sufficient to suppress carbohydrate-responsive-element-binding protein (ChREBP, a master lipogenic regulator), and fatty acid synthase (FASN), its effector lipogenic gene. Stable FASN knockdown was sufficient to induce EMT, stimulate migration and extravasation in vitro. FASN silencing enhanced lung metastasis and death in vivo. These data suggest that a metabolic transition that suppresses lipogenesis and favors energy production is an essential component of TGFβ1-induced EMT and metastasis.

PMID:
25284588
PMCID:
PMC4387121
DOI:
10.1038/onc.2014.321
[Indexed for MEDLINE]
Free PMC Article

Supplemental Content

Full text links

Icon for Nature Publishing Group Icon for PubMed Central
Loading ...
Support Center