Abstract
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.
Highlights
Mammalian cells can respond differently to wide ranges of oxygen through alterations in both their metabolic states and growth rates [1, 2]
We found that cyclin D1 expression in DN-Hypoxia-inducible factor (HIF) stable transfectant was significantly increased, at both RNA and protein level, in Beas-2B cells exposed to arsenite (Fig. 2A and B), which indicates the negative regulation of cyclin D1 by hypoxia-inducible factor-1 (HIF-1)
We showed the negative regulation of cyclin D1 by HIF-1 in human Beas-2B cells, 293T cells, A549 cancer cells, and even in malignant tissue
Summary
Mammalian cells can respond differently to wide ranges of oxygen through alterations in both their metabolic states and growth rates [1, 2]. Cells undergo a variety of biological changes upon hypoxic conditions, including activation of signaling pathways that regulate proliferation, angiogenesis, and death. The primary factor mediating this response is hypoxia-inducible factor-1 HIF-1 was first discovered by the identification of a hypoxia response element (HRE) in the 3′ enhancer of the gene for erythropoietin, a hormone that stimulates erythrocyte proliferation [4, 5]. Authors' Affiliations: 1The International Cooperation Laboratory on Signal Transduction of Eastern Hepatobiliary Surgery Institute and 2The Department of Gastroenterology of Changzheng Hospital, Second Military Medical University, Shanghai, China. Note: Supplementary data for this article are available at Cancer Research Online (http://cancerres.aacrjournals.org/).
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