Induction of human endometrial cancer cell senescence through modulation of HIF-1α activity by EGLN1

Hidenori Kato, Takafumi Inoue, Kazuo Asanoma, Chie Nishimura, Takao Matsuda, Norio Wake

Research output: Contribution to journalArticle

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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 ehr. 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 wav 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.

Original languageEnglish
Pages (from-to)1144-1153
Number of pages10
JournalInternational Journal of Cancer
Volume118
Issue number5
DOIs
Publication statusPublished - Mar 1 2006

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Cell Aging
Endometrial Neoplasms
Genes
Prolyl Hydroxylases
Uterine Neoplasms
Mutation
Loss of Heterozygosity
Chromosomes, Human, Pair 1
Ubiquitination
Human Chromosomes
Hydroxylation
Gene Frequency
Sarcoma
Microsatellite Repeats
Signal Transduction
Chromosomes
Observation
Cell Line
Neoplasms

All Science Journal Classification (ASJC) codes

  • Oncology
  • Cancer Research

Cite this

Induction of human endometrial cancer cell senescence through modulation of HIF-1α activity by EGLN1. / Kato, Hidenori; Inoue, Takafumi; Asanoma, Kazuo; Nishimura, Chie; Matsuda, Takao; Wake, Norio.

In: International Journal of Cancer, Vol. 118, No. 5, 01.03.2006, p. 1144-1153.

Research output: Contribution to journalArticle

Kato, Hidenori ; Inoue, Takafumi ; Asanoma, Kazuo ; Nishimura, Chie ; Matsuda, Takao ; Wake, Norio. / Induction of human endometrial cancer cell senescence through modulation of HIF-1α activity by EGLN1. In: International Journal of Cancer. 2006 ; Vol. 118, No. 5. pp. 1144-1153.
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