This Article Full Text Full Text (PDF) Alert me when this article is cited Alert me if a correction is posted Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Furuta, E. Articles by Watabe, K. Search for Related Content PubMed PubMed Citation Articles by Furuta, E. Articles by Watabe, K.

Fatty Acid Synthase Gene Is Up-regulated by Hypoxia via Activation of Akt and Sterol Regulatory Element Binding Protein-1

¹ Department of Medical Microbiology, Immunology, and Cell Biology, Southern Illinois University School of Medicine, Springfield, Illinois; ² Department of Developmental Biology, Stanford University, School of Medicine, Stanford, California; ³ Akita Red Cross Hospital, Akita, Japan; and ⁴ Ludwig Institute for Cancer Research, Uppsala University, Biomedical Center, Uppsala, Sweden

Requests for reprints: Kounosuke Watabe, Department of Medical Microbiology, Immunology and Cell Biology, Southern Illinois University School of Medicine, 801 North Rutledge Street, P.O. Box 19626, Springfield, IL 62794-9626. Phone: 217-545-3969; Fax: 217-545-3227; E-mail: kwatabe{at}siumed.edu.

Key Words: fatty acid synthase • hypoxia • chemoresistance

The fatty acid synthase (FAS) gene is significantly up-regulated in various types of cancers, and blocking the FAS expression results in apoptosis of tumor cells. Therefore, FAS is considered to be an attractive target for anticancer therapy. However, the molecular mechanism by which the FAS gene is up-regulated in tumor cells is poorly understood. We found that FAS was significantly up-regulated by hypoxia, which was also accompanied by reactive oxygen species (ROS) generation in human breast cancer cell lines. The FAS expression was also activated by H₂O₂, whereas N-acetyl-L-cystein, a ROS inhibitor, suppressed the expression. We also found that the hypoxia significantly up-regulated sterol regulatory–element binding protein (SREBP)-1, the major transcriptional regulator of the FAS gene, via phosphorylation of Akt followed by activation of hypoxia-inducible factor 1 (HIF1). Moreover, our results of reporter assay and chromatin immunoprecipitation analysis indicate that SREBP-1 strongly bound to the SREBP binding site/E-box sequence on the FAS promoter under hypoxia. In our xenograft mouse model, FAS was strongly expressed in the hypoxic regions of the tumor. In addition, our results of immunohistochemical analysis for human breast tumor specimens indicate that the expressions of both FAS and SREBP-1 were colocalized with hypoxic regions in the tumors. Furthermore, we found that hypoxia-induced chemoresistance to cyclophosphamide was partially blocked by a combination of FAS inhibitor and cyclophosphamide. Taken together, our results indicate that FAS gene is up-regulated by hypoxia via activation of the Akt and HIF1 followed by the induction of the SREBP-1 gene, and that hypoxia-induced chemoresistance is partly due to the up-regulation of FAS. [Cancer Res 2008;68(4):1003–11]

This article has been cited by other articles:

				C.-Y. Park, H.-J. Jun, T. Wakita, J. H. Cheong, and S. B. Hwang Hepatitis C Virus Nonstructural 4B Protein Modulates Sterol Regulatory Element-binding Protein Signaling via the AKT Pathway J. Biol. Chem., April 3, 2009; 284(14): 9237 - 9246. [Abstract] [Full Text] [PDF]

				T. Migita, S. Ruiz, A. Fornari, M. Fiorentino, C. Priolo, G. Zadra, F. Inazuka, C. Grisanzio, E. Palescandolo, E. Shin, et al. Fatty Acid Synthase: A Metabolic Enzyme and Candidate Oncogene in Prostate Cancer J Natl Cancer Inst, April 1, 2009; 101(7): 519 - 532. [Abstract] [Full Text] [PDF]

				S. Ogino, K. Nosho, J. A. Meyerhardt, G. J. Kirkner, A. T. Chan, T. Kawasaki, E. L. Giovannucci, M. Loda, and C. S. Fuchs Cohort Study of Fatty Acid Synthase Expression and Patient Survival in Colon Cancer J. Clin. Oncol., December 10, 2008; 26(35): 5713 - 5720. [Abstract] [Full Text] [PDF]

				A. L. Risinger, E. M. Jackson, L. A. Polin, G. L. Helms, D. A. LeBoeuf, P. A. Joe, E. Hopper-Borge, R. F. Luduena, G. D. Kruh, and S. L. Mooberry The Taccalonolides: Microtubule Stabilizers That Circumvent Clinically Relevant Taxane Resistance Mechanisms Cancer Res., November 1, 2008; 68(21): 8881 - 8888. [Abstract] [Full Text] [PDF]

				S. M. Choi, H.-J. Cho, H. Cho, K. H. Kim, J. B. Kim, and H. Park Stra13/DEC1 and DEC2 inhibit sterol regulatory element binding protein-1c in a hypoxia-inducible factor-dependent mechanism Nucleic Acids Res., November 1, 2008; 36(20): 6372 - 6385. [Abstract] [Full Text] [PDF]