title: Suppression of cyclin D1 by hypoxia-inducible factor-1 via direct mechanism inhibits the proliferation and 5-fluorouracil-induced apoptosis of A549 cells.
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.
authors.affiliation: The International Cooperation Laboratory on Signal Transduction of Eastern Hepatobiliary Surgery Institute, Second Military Medical University, Shanghai, China.
authors.forename: Wen
authors.initials: W
authors.lastname: Wen
authors.forename: Jin
authors.initials: J
authors.lastname: Ding
authors.forename: Wen
authors.initials: W
authors.lastname: Sun
authors.forename: Kun
authors.initials: K
authors.lastname: Wu
authors.forename: Beifang
authors.initials: B
authors.lastname: Ning
authors.forename: Wenfeng
authors.initials: W
authors.lastname: Gong
authors.forename: Guoping
authors.initials: G
authors.lastname: He
authors.forename: Shanna
authors.initials: S
authors.lastname: Huang
authors.forename: Xinyu
authors.initials: X
authors.lastname: Ding
authors.forename: Peipei
authors.initials: P
authors.lastname: Yin
authors.forename: Lei
authors.initials: L
authors.lastname: Chen
authors.forename: Qiong
authors.initials: Q
authors.lastname: Liu
authors.forename: Weifen
authors.initials: W
authors.lastname: Xie
authors.forename: Hongyang
authors.initials: H
authors.lastname: Wang
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000187:drug effects* / Q000502:physiology; D048708:Cell Growth Processes / Q000502:physiology; D015687:Cell Hypoxia / Q000502:physiology; D045744:Cell Line, Tumor; D019938:Cyclin D1 / Q000096:biosynthesis / Q000378:metabolism*; D005347:Fibroblasts / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D005472:Fluorouracil / Q000494:pharmacology*; D016193:G1 Phase; D006801:Humans; D051793:Hypoxia-Inducible Factor 1 / Q000378:metabolism*; D008175:Lung Neoplasms / Q000188:drug therapy / Q000378:metabolism / Q000473:pathology; D051379:Mice; D016196:S Phase
chemical_list: D051793:Hypoxia-Inducible Factor 1; D019938:Cyclin D1; D005472:Fluorouracil