Molecules and Cells

Korean Society for Molecular and Cellular Biology (한국분자세포생물학회)
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Hypoxia Inducible Factor-1α Directly Regulates Nuclear Clusterin Transcription by Interacting with Hypoxia Response Elements in the Clusterin Promoter

  • Park, Jeongsook (Department of Anatomy and Neurobiology, Institute of Health Science, Medical Research Center for Neural Dysfunction, School of Medicine, Gyeongsang National University) ;
  • Park, So Yun (Department of Anatomy and Neurobiology, Institute of Health Science, Medical Research Center for Neural Dysfunction, School of Medicine, Gyeongsang National University) ;
  • Shin, Eunkyung (Department of Anatomy and Neurobiology, Institute of Health Science, Medical Research Center for Neural Dysfunction, School of Medicine, Gyeongsang National University) ;
  • Lee, Sun Hee (Department of Anatomy and Neurobiology, Institute of Health Science, Medical Research Center for Neural Dysfunction, School of Medicine, Gyeongsang National University) ;
  • Kim, Yoon Sook (Department of Anatomy and Neurobiology, Institute of Health Science, Medical Research Center for Neural Dysfunction, School of Medicine, Gyeongsang National University) ;
  • Lee, Dong Hoon (Department of Anatomy and Neurobiology, Institute of Health Science, Medical Research Center for Neural Dysfunction, School of Medicine, Gyeongsang National University) ;
  • Roh, Gu Seob (Department of Anatomy and Neurobiology, Institute of Health Science, Medical Research Center for Neural Dysfunction, School of Medicine, Gyeongsang National University) ;
  • Kim, Hyun Joon (Department of Anatomy and Neurobiology, Institute of Health Science, Medical Research Center for Neural Dysfunction, School of Medicine, Gyeongsang National University) ;
  • Kang, Sang Soo (Department of Anatomy and Neurobiology, Institute of Health Science, Medical Research Center for Neural Dysfunction, School of Medicine, Gyeongsang National University) ;
  • Cho, Gyeong Jae (Department of Anatomy and Neurobiology, Institute of Health Science, Medical Research Center for Neural Dysfunction, School of Medicine, Gyeongsang National University) ;
  • Jeong, Bo-Young (Department of Food & Nutrition, College of Natural Sciences, Gyeongsang National University) ;
  • Kim, Hwajin (Department of Anatomy and Neurobiology, Institute of Health Science, Medical Research Center for Neural Dysfunction, School of Medicine, Gyeongsang National University) ;
  • Choi, Wan Sung (Department of Anatomy and Neurobiology, Institute of Health Science, Medical Research Center for Neural Dysfunction, School of Medicine, Gyeongsang National University)
  • Received : 2013.11.21
  • Accepted : 2013.12.30
  • Published : 2014.02.28
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Abstract

Differential transcription of the clusterin (CLU) gene yields two CLU isoforms, a nuclear form (nCLU) and a secretory form (sCLU), which play crucial roles in prostate tumorigenesis. Pro-apoptotic nCLU and anti-apoptotic sCLU have opposite effects and are differentially expressed in normal and cancer cells; however, their regulatory mechanisms at the transcriptional level are not yet known. Here, we examined the transcriptional regulation of nCLU in response to hypoxia. We identified three putative hypoxia response elements (HREs) in the human CLU promoter between positions -806 and +51 bp. Using a luciferase reporter, electrophoretic gel mobility shift, and chromatin immunoprecipitation assays, we further showed that hypoxia-inducible factor-$1{\alpha}$ (HIF-$1{\alpha}$) bound directly to these sites and activated transcription. Exposure to the hypoxia-mimetic compound $CoCl_2$, incubation under 1% $O_2$ conditions, or overexpression of HIF-$1{\alpha}$ enhanced nCLU expression and induced apoptosis in human prostate cancer PC3M cells. However, LNCaP prostate cancer cells were resistant to hypoxia-induced cell death. Methylation-specific PCR analysis revealed that the CLU promoter in PC3M cells was not methylated; in contrast, the CLU promoter in LNCap cells was methylated. Co-treatment of LNCaP cells with $CoCl_2$ and a demethylating agent promoted apoptotic cell death through the induction of nCLU. We conclude that nCLU expression is regulated by direct binding of HIF-$1{\alpha}$ to HRE sites and is epigenetically controlled by methylation of its promoter region.

Keywords

References

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