title: Regulation of hypoxia-inducible factor 1α (HIF-1α) by lysophosphatidic acid is dependent on interplay between p53 and Krüppel-like factor 5.
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.
authors.affiliation: From the Division of Digestive Diseases, Department of Medicine, Emory University, Atlanta, Georgia 30322.
authors.forename: Sei-Jung
authors.initials: SJ
authors.lastname: Lee
authors.affiliation: From the Division of Digestive Diseases, Department of Medicine, Emory University, Atlanta, Georgia 30322.
authors.forename: Yi Ran
authors.initials: YR
authors.lastname: No
authors.affiliation: the Division of Gastroenterology, Department of Internal Medicine, University of Michigan, Ann Arbor, Michigan 48109.
authors.forename: Duyen T
authors.initials: DT
authors.lastname: Dang
authors.affiliation: the Division of Hematology and Oncology, Department of Medicine, University of Florida, Gainesville, Florida 32610.
authors.forename: Long H
authors.initials: LH
authors.lastname: Dang
authors.affiliation: the Department of Medicine, Stony Brook University School of Medicine, Stony Brook, New York 11794.
authors.forename: Vincent W
authors.initials: VW
authors.lastname: Yang
authors.affiliation: the Winship Cancer Institute, Emory University, Atlanta, Georgia 30322, and; the Department of Radiology, Emory University, Atlanta, Georgia 30322.
authors.forename: Hyunsuk
authors.initials: H
authors.lastname: Shim
authors.affiliation: From the Division of Digestive Diseases, Department of Medicine, Emory University, Atlanta, Georgia 30322,; the Winship Cancer Institute, Emory University, Atlanta, Georgia 30322, and. Electronic address: ccyun@emory.edu.
authors.forename: C Chris
authors.initials: CC
authors.lastname: Yun
mesh_terms: D045744:Cell Line, Tumor; D003110:Colonic Neoplasms / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D020868:Gene Silencing; D006801:Humans; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000235:genetics / Q000378:metabolism*; D051741:Kruppel-Like Transcription Factors / Q000235:genetics / Q000378:metabolism*; D008246:Lysophospholipids / Q000235:genetics / Q000378:metabolism*; D009154:Mutation; D011485:Protein Binding; D020218:Response Elements; D015534:Trans-Activators / Q000235:genetics / Q000378:metabolism*; D016159:Tumor Suppressor Protein p53 / Q000235:genetics / Q000378:metabolism*
chemical_list: C497442:HIF1A protein, human; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; C492214:KLF5 protein, human; D051741:Kruppel-Like Transcription Factors; D008246:Lysophospholipids; C495901:TP53 protein, human; D015534:Trans-Activators; D016159:Tumor Suppressor Protein p53; C032881:lysophosphatidic acid
keywords: Colon Cancer; G Protein-coupled Receptor (GPCR); Hypoxia-inducible Factor (HIF); Lysophospholipid; Proliferation