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Hypoxia Inducible Factor-1α Directly Regulates Nuclear Clusterin Transcription by Interacting with Hypoxia Response Elements in the Clusterin Promoter

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 cance...

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Autores principales: Park, Jeongsook, Park, So Yun, Shin, Eunkyung, Lee, Sun Hee, Kim, Yoon Sook, Lee, Dong Hoon, Roh, Gu Seob, Kim, Hyun Joon, Kang, Sang Soo, Cho, Gyeong Jae, Jeong, Bo-Young, Kim, Hwajin, Choi, Wan Sung
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Korea Society for Molecular and Cellular Biology 2014
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3935631/
https://www.ncbi.nlm.nih.gov/pubmed/24599003
http://dx.doi.org/10.14348/molcells.2014.2349
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author Park, Jeongsook
Park, So Yun
Shin, Eunkyung
Lee, Sun Hee
Kim, Yoon Sook
Lee, Dong Hoon
Roh, Gu Seob
Kim, Hyun Joon
Kang, Sang Soo
Cho, Gyeong Jae
Jeong, Bo-Young
Kim, Hwajin
Choi, Wan Sung
author_facet Park, Jeongsook
Park, So Yun
Shin, Eunkyung
Lee, Sun Hee
Kim, Yoon Sook
Lee, Dong Hoon
Roh, Gu Seob
Kim, Hyun Joon
Kang, Sang Soo
Cho, Gyeong Jae
Jeong, Bo-Young
Kim, Hwajin
Choi, Wan Sung
author_sort Park, Jeongsook
collection PubMed
description 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-1α (HIF-1α) bound directly to these sites and activated transcription. Exposure to the hypoxiamimetic compound CoCl(2), incubation under 1% O(2) conditions, or overexpression of HIF-1α 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-1α to HRE sites and is epigenetically controlled by methylation of its promoter region.
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spelling pubmed-39356312014-02-26 Hypoxia Inducible Factor-1α Directly Regulates Nuclear Clusterin Transcription by Interacting with Hypoxia Response Elements in the Clusterin Promoter Park, Jeongsook Park, So Yun Shin, Eunkyung Lee, Sun Hee Kim, Yoon Sook Lee, Dong Hoon Roh, Gu Seob Kim, Hyun Joon Kang, Sang Soo Cho, Gyeong Jae Jeong, Bo-Young Kim, Hwajin Choi, Wan Sung Mol Cells 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-1α (HIF-1α) bound directly to these sites and activated transcription. Exposure to the hypoxiamimetic compound CoCl(2), incubation under 1% O(2) conditions, or overexpression of HIF-1α 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-1α to HRE sites and is epigenetically controlled by methylation of its promoter region. Korea Society for Molecular and Cellular Biology 2014-02-28 2014-02-19 /pmc/articles/PMC3935631/ /pubmed/24599003 http://dx.doi.org/10.14348/molcells.2014.2349 Text en © The Korean Society for Molecular and Cellular Biology. All rights reserved. This is an open-access article distributed under the terms of the Creative Commons Attribution-NonCommercial-ShareAlike 3.0 Unported License. To view a copy of this license, visit http://creativecommons.org/licenses/by-nc-sa/3.0/.
spellingShingle Park, Jeongsook
Park, So Yun
Shin, Eunkyung
Lee, Sun Hee
Kim, Yoon Sook
Lee, Dong Hoon
Roh, Gu Seob
Kim, Hyun Joon
Kang, Sang Soo
Cho, Gyeong Jae
Jeong, Bo-Young
Kim, Hwajin
Choi, Wan Sung
Hypoxia Inducible Factor-1α Directly Regulates Nuclear Clusterin Transcription by Interacting with Hypoxia Response Elements in the Clusterin Promoter
title Hypoxia Inducible Factor-1α Directly Regulates Nuclear Clusterin Transcription by Interacting with Hypoxia Response Elements in the Clusterin Promoter
title_full Hypoxia Inducible Factor-1α Directly Regulates Nuclear Clusterin Transcription by Interacting with Hypoxia Response Elements in the Clusterin Promoter
title_fullStr Hypoxia Inducible Factor-1α Directly Regulates Nuclear Clusterin Transcription by Interacting with Hypoxia Response Elements in the Clusterin Promoter
title_full_unstemmed Hypoxia Inducible Factor-1α Directly Regulates Nuclear Clusterin Transcription by Interacting with Hypoxia Response Elements in the Clusterin Promoter
title_short Hypoxia Inducible Factor-1α Directly Regulates Nuclear Clusterin Transcription by Interacting with Hypoxia Response Elements in the Clusterin Promoter
title_sort hypoxia inducible factor-1α directly regulates nuclear clusterin transcription by interacting with hypoxia response elements in the clusterin promoter
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3935631/
https://www.ncbi.nlm.nih.gov/pubmed/24599003
http://dx.doi.org/10.14348/molcells.2014.2349
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