Regulation of Hypoxia-inducible Factor 1 alpha (HIF-1 alpha) by Lysophosphatidic Acid Is Dependent on Interplay between p53 and Kruppel-like Factor 5

• Type of Material: Article
• Authors: Sei-Jung Lee, Emory University; Yi Ran No, Emory University; Duyen T. Dang, University of Michigan; Long H. Dang, University of Florida; Vincent W. Yang, Stony Brook University; Hyunsuk Shim, Emory University; Chang-Hyon Yun, Emory University
• Language: English
• Date: 2013-08-30
• Publisher: American Society for Biochemistry and Molecular Biology
• Publication Version: Final Published Version
• Copyright Statement: © 2013 by The American Society for Biochemistry and Molecular Biology, Inc.
• Final Published Version (URL): http://dx.doi.org/10.1074/jbc.M113.489708
• Title of Journal or Parent Work: Journal of Biological Chemistry
• ISSN: 0021-9258
• Volume: 288
• Issue: 35
• Start Page: 25244
• End Page: 25253
• Grant/Funding Information: Use of the confocal microscope was supported by the Emory Digestive Diseases Research Development Center under National Institutes of Health Grant R24 DK064399.; This work was also supported by a Senior Research Award from the Crohn's and Colitis Foundation of America (to C. C. Y.).; This work was supported, in whole or in part, by National Institutes of Health Grant R01 DK071597.
• Keywords: PROTEIN; G Protein-coupled Receptor (GPCR); LPA RECEPTORS; COLORECTAL-CANCER; BIOCHEMISTRY & MOLECULAR BIOLOGY; EPITHELIAL-CELLS; Proliferation; INDUCTION; Life Sciences & Biomedicine; GROWTH-FACTOR EXPRESSION; Lysophospholipid; Biochemistry & Molecular Biology; MDM2; Science & Technology; Hypoxia-inducible Factor (HIF); ACTIVATION; Colon Cancer; CELLULAR-RESPONSE; COLON-CANCER CELLS
• Research Categories: Health Sciences, Oncology; Health Sciences, General; Health Sciences, Radiology

Abstract

Hypoxia-inducible factor 1α (HIF-1α) and p53 are pivotal regulators of tumor growth. Lysophosphatidic acid (LPA) is a lipid mediator that functions as a mitogen by acting through LPA receptors. We have shown previously that LPA stimulates HIF-1α expression in colon cancer cells. To determine the mechanism of HIF-1α induction by LPA, we compared the effect of LPA on HIF-1α in several colon cancer cell lines. LPA transcriptionally induced HIF-1α in colon cancer cells. HIF-1α induction was observed in cells expressing WT p53, where LPA decreased p53 expression. However, LPA failed to induce HIF-1α when the p53 gene was mutated. A decrease in p53 expression was dependent on induction of p53-specific E3 ubiquitin ligase Mdm2 by LPA. Krüppel-like factor 5 (KLF5) is an effector of LPA-induced proliferation of colon cancer cells. Because HIF-1α was necessary for LPA-induced growth of colon cancer cells, we determined the relationship between KLF5 and HIF-1α by a loss-of-function approach. Silencing of KLF5 inhibited LPA-induced HIF-1α induction, suggesting that KLF5 is an upstream regulator of HIF-1α. KLF5 and p53 binding to the Hif1α promoter was assessed by ChIP assay. LPA increased the occupancy of the Hif1α promoter by KLF5, while decreasing p53 binding. Transfection of HCT116 cells with KLF5 or p53 attenuated the binding of the other transcription factor. These results identify KLF5 as a transactivator of HIF-1α and show that LPA regulates HIF-1α by dynamically modulating its interaction with KLF5 and p53.