title: Induction of human endometrial cancer cell senescence through modulation of HIF-1alpha activity by EGLN1.
abstract: Previous observations indicate that transfer of human chromosome (chr.) 1 induces senescence of endometrial cancer cells. To identify the gene(s) responsible for the senescence, we first analyzed the structural integrity of the introduced chr. 1 in immortal revertant from chr.1-transferred HHUA cells. The data demonstrated a correlation between nonrandom deletions within the 1q31-qter region and reversion to immortality. Next, by using a panel of 12 microsatellite markers, we found high frequencies of loss of heterozygosity in the particular 1q region (1q41-42), in surgically removed samples. Then, we screened the genetic mutation of the genes involved in this region, with endometrial cancer panel. Among them, EGLN1, that is a member of prolyl hydroxylase and can facilitate HIF-1 degradation by ubiquitination through the hydroxylation of HIF-1, was mutated at significantly higher frequencies (12/20, 60%). Introduction of wild-type EGLN1 into endometrial cancer cell lines (HHUA, Ishikawa and HWCA), that carry EGLN1 gene mutations induced senescence. This was invoked through the negative regulation of HIF-1 expression. In addition, alternative way of negative regulation of HIF-1 by Factor inhibiting HIF-1(FIH), SiRNA against HIF-1, and HIF-1 inhibitor, YC-1, could also induce senescence. Thus, EGLN1 can be considered as a candidate tumor suppressor on chr. 1q, and our observation could open the new aspect in exploring the machinery of senescence induction associated with HIF-1 signal transduction. These results also suggested the availability of negative regulation of HIF-1 signals for uterine cancer treatment, especially for uterine sarcomas that have worse prognosis and show a high frequency of EGLN1 gene abnormality.
authors.affiliation: Department of Molecular Genetics, Division of Molecular and Cell Therapeutics, Medical Institute of Bioregulation, Kyushu University, Tsurumihara 4546, Beppu City, Oita 874-0838, Japan. hidekato@tsurumi.beppu.kyushu-u.ac.jp
authors.forename: Hidenori
authors.initials: H
authors.lastname: Kato
authors.forename: Takafumi
authors.initials: T
authors.lastname: Inoue
authors.forename: Kazuo
authors.initials: K
authors.lastname: Asanoma
authors.forename: Chie
authors.initials: C
authors.lastname: Nishimura
authors.forename: Takao
authors.initials: T
authors.lastname: Matsuda
authors.forename: Norio
authors.initials: N
authors.lastname: Wake
mesh_terms: D000818:Animals; D045744:Cell Line, Tumor; D016922:Cellular Senescence / Q000502:physiology*; D002878:Chromosomes, Human, Pair 1 / Q000235:genetics; D016889:Endometrial Neoplasms / Q000235:genetics / Q000378:metabolism* / Q000473:pathology*; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000235:genetics / Q000378:metabolism*; D064799:Hypoxia-Inducible Factor-Proline Dioxygenases; D017874:Immediate-Early Proteins / Q000235:genetics / Q000378:metabolism*; D051379:Mice; D009154:Mutation / Q000235:genetics; D010641:Phenotype; D011393:Procollagen-Proline Dioxygenase / Q000235:genetics / Q000378:metabolism*; D025521:Tumor Suppressor Proteins / Q000235:genetics
chemical_list: D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D017874:Immediate-Early Proteins; D025521:Tumor Suppressor Proteins; C490190:EGLN1 protein, human; D011393:Procollagen-Proline Dioxygenase; D064799:Hypoxia-Inducible Factor-Proline Dioxygenases