Document Detail


Suppression of cyclin D1 by hypoxia-inducible factor-1 via direct mechanism inhibits the proliferation and 5-fluorouracil-induced apoptosis of A549 cells.
MedLine Citation:
PMID:  20179204     Owner:  NLM     Status:  MEDLINE    
Abstract/OtherAbstract:
Hypoxia-inducible factor (HIF) and cyclin D1 are both key mediators of cell growth and proliferation in normal and cancer cells. However, the interrelation between HIF and cyclin D1 remains unclear. In the present study, we observed the inverse correlation between cyclin D1 and HIF-1 in hypoxia condition. Overexpression of the dominant negative mutant of HIF-1alpha (DN-HIF) significantly enhanced cyclin D1 expression upon hypoxia or arsenite exposure, suggesting the negative regulation of cyclin D1 by HIF-1. Furthermore, we found that the impairment of HIF-1 increased cyclin D1 expression in A549 pulmonary cancer cells, which in turn promoted G1-S cell cycle transition and cell proliferation. Cyclin D1 expression was increased in s.c. xenograft of DN-HIF stably transfected A549 cells in nude mice compared with that of control cells. Chromatin immunoprecipitation assay revealed that HIF-1 was able to directly bind to the promoter region of cyclin D1, which indicates that the negative regulation of cyclin D1 by HIF-1 is through a direct mechanism. Inhibition of histone deacetylase (HDAC) by pretreatment of cells with trichostatin A or specific knockdown of HDAC7 by its shRNA antagonized the suppression of cyclin D1 by HIF-1, suggesting that HDAC7 is required for HIF-1-mediated cyclin D1 downregulation. Moreover, we found that 5-fluorouracil-triggered apoptosis of DN-HIF-transfected A549 cells was reduced by sicyclin D1 (cyclin D1-specific interference RNA) introduction, suggesting that clinical observation of HIF-1 overexpression-associated chemoresistance might be, at least partially, due to the negative regulation of cyclin D1.
Authors:
Wen Wen; Jin Ding; Wen Sun; Kun Wu; Beifang Ning; Wenfeng Gong; Guoping He; Shanna Huang; Xinyu Ding; Peipei Yin; Lei Chen; Qiong Liu; Weifen Xie; Hongyang Wang
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Publication Detail:
Type:  Journal Article; Research Support, Non-U.S. Gov't     Date:  2010-02-23
Journal Detail:
Title:  Cancer research     Volume:  70     ISSN:  1538-7445     ISO Abbreviation:  Cancer Res.     Publication Date:  2010 Mar 
Date Detail:
Created Date:  2010-03-02     Completed Date:  2010-04-08     Revised Date:  -    
Medline Journal Info:
Nlm Unique ID:  2984705R     Medline TA:  Cancer Res     Country:  United States    
Other Details:
Languages:  eng     Pagination:  2010-9     Citation Subset:  IM    
Affiliation:
The International Cooperation Laboratory on Signal Transduction of Eastern Hepatobiliary Surgery Institute, Second Military Medical University, Shanghai, China.
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MeSH Terms
Descriptor/Qualifier:
Animals
Apoptosis / drug effects*,  physiology
Cell Growth Processes / physiology
Cell Hypoxia / physiology
Cell Line, Tumor
Cyclin D1 / biosynthesis,  metabolism*
Fibroblasts / cytology,  drug effects,  metabolism
Fluorouracil / pharmacology*
G1 Phase
Humans
Hypoxia-Inducible Factor 1 / metabolism*
Lung Neoplasms / drug therapy,  metabolism,  pathology
Mice
S Phase
Chemical
Reg. No./Substance:
0/Hypoxia-Inducible Factor 1; 136601-57-5/Cyclin D1; 51-21-8/Fluorouracil

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