Fatty acid synthase (FASN) and ATP-citrate lyase, key enzymes of de novo lipogenesis, are significantly upregulated and activated in many cancers and portend poor prognosis. Even though the role of lipogenesis in providing proliferative and survival advantages to cancer cells has been described, the impact of aberrant activation of lipogenic enzymes on cancer progression remains unknown. In this study, we found that elevated expression of FASN is associated with advanced stages of colorectal cancer (CRC) and liver metastasis, suggesting that it may play a role in progression of CRC to metastatic disease. Targeted inhibition of lipogenic enzymes abolished expression of CD44, a transmembrane protein associated with metastases in several cancers including CRC. In addition, inhibition of lipogenic enzymes and reduced expression of CD44 attenuated the activation of MET, Akt, FAK, and paxillin, which are known to regulate adhesion, migration, and invasion. These changes were consistent with an observed decrease in migration and adhesion of CRC cells in functional assays and with reorganization of actin cytoskeleton upon FASN inhibition. Despite the modest effect of FASN inhibition on tumor growth in xenografts, attenuation of lipogenesis completely abolished establishment of hepatic metastasis and formation of secondary metastasis. Together, our findings suggest that targeting de novo lipogenesis may be a potential treatment strategy for advanced CRC.

Document Type


Publication Date


Notes/Citation Information

Published in Cancer Research, v. 72, issue 6, p. 1504-1517.

© 2012 American Association for Cancer Research.

The copyright holder has granted the permission for posting the article here.

The document available for download is the authors' post-peer-review final draft of the article.

Digital Object Identifier (DOI)


Funding Information

This work was supported by P20CA1530343 (GI SPORE; B.M. Evers), GM50388 and P20RR021954 (A.J. Morris).

Related Content

Supplementary data for this article are available at Cancer Research Online (http://cancerres.aacrjournals.org/).