HOP/OB1/NECC1 promoter DNA is frequently hypermethylated and involved in tumorigenic ability in esophageal squamous cell carcinoma

Keishi Yamashita, Myoung Sook Kim, Hannah Lui Park, Yutaka Tokumaru, Motonobu Osada, Hiroshi Inoue, Masaki Mori, David Sidransky

Research output: Contribution to journalArticle

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Abstract

Promoter DNA hypermethylation with gene silencing is a common feature of human cancer, and cancer-prone methylation is believed to be a landmark of tumor suppressor genes (TSG). Identification of novel methylated genes would not only aid in the development of tumor markers but also elucidate the biological behavior of human cancers. We identified several epigenetically silenced candidate TSGs by pharmacologic unmasking of esophageal squamous cell carcinoma (ESCC) cell lines by demethylating agents (5-aza-2′-deoxycitidine and trichostatin A) combined with ESCC expression profiles using expression microarray. HOP/OB1/NECC1 was identified as an epigenetically silenced candidate TSG and further examined for (a) expression status, (b) methylation status, and (c) functional involvement in cancer cell lines. (a) The HOP gene encodes two putative promoters (promoters A and B) associated with two open reading frames (HOPα and HOPβ, respectively), and HOPα and HOPβ were both down-regulated in ESCC independently. (b) Promoter B harbors dense CpG islands, in which we found dense methylation in a cancer-prone manner (55% in tumor tissues by TaqMan methylation-specific PCR), whereas promoter A does not harbor CpG islands. HOPβ silencing was associated with DNA methylation of promoter B in nine ESCC cell lines tested, and reactivated by optimal conditions of demethylating agents, whereas HOPα silencing was not reactivated by such treatments. Forced expression of HOP suppressed tumorigenesis in soft agar in four different squamous cell carcinoma cell lines. More convincingly, RNA interference knockdown of HOP in TE2 cells showed drastic restoration of the oncogenic phenotype. In conclusion, HOP is a putative TSG that harbors tumor inhibitory activity, and we for the first time showed that the final shutdown process of HOP expression is linked to promoter DNA hypermethylation under the double control of the discrete promoter regions in cancer.

Original languageEnglish
Pages (from-to)31-41
Number of pages11
JournalMolecular Cancer Research
Volume6
Issue number1
DOIs
Publication statusPublished - Jan 1 2008

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Aptitude
DNA
Methylation
Neoplasms
Tumor Suppressor Genes
Cell Line
CpG Islands
trichostatin A
Esophageal Squamous Cell Carcinoma
Gene Silencing
DNA Methylation
Tumor Biomarkers
RNA Interference
Genetic Promoter Regions
Open Reading Frames
Genes
Agar
Squamous Cell Carcinoma
Carcinogenesis
Phenotype

All Science Journal Classification (ASJC) codes

  • Molecular Biology
  • Oncology
  • Cancer Research

Cite this

HOP/OB1/NECC1 promoter DNA is frequently hypermethylated and involved in tumorigenic ability in esophageal squamous cell carcinoma. / Yamashita, Keishi; Kim, Myoung Sook; Park, Hannah Lui; Tokumaru, Yutaka; Osada, Motonobu; Inoue, Hiroshi; Mori, Masaki; Sidransky, David.

In: Molecular Cancer Research, Vol. 6, No. 1, 01.01.2008, p. 31-41.

Research output: Contribution to journalArticle

Yamashita, Keishi ; Kim, Myoung Sook ; Park, Hannah Lui ; Tokumaru, Yutaka ; Osada, Motonobu ; Inoue, Hiroshi ; Mori, Masaki ; Sidransky, David. / HOP/OB1/NECC1 promoter DNA is frequently hypermethylated and involved in tumorigenic ability in esophageal squamous cell carcinoma. In: Molecular Cancer Research. 2008 ; Vol. 6, No. 1. pp. 31-41.
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AU - Kim, Myoung Sook

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AU - Tokumaru, Yutaka

AU - Osada, Motonobu

AU - Inoue, Hiroshi

AU - Mori, Masaki

AU - Sidransky, David

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