FHL1 on chromosome X is a single-hit gastrointestinal tumor-suppressor gene and contributes to the formation of an epigenetic field defect

被引：42

作者：

Asada, K. ^{[1
]}

Ando, T. ^{[1
,2
]}

Niwa, T. ^{[1
]}

Nanjo, S. ^{[1
]}

Watanabe, N. ^{[1
]}

Okochi-Takada, E. ^{[1
]}

Yoshida, T. ^{[1
]}

Miyamoto, K. ^{[3
,4
]}

Enomoto, S. ^{[5
]}

Ichinose, M. ^{[5
]}

Tsukamoto, T. ^{[6
]}

Ito, S. ^{[7
]}

Tatematsu, M. ^{[6
]}

Sugiyama, T. ^{[2
]}

Ushijima, T. ^{[1
]}

机构：

[1] Natl Canc Ctr, Div Epigen, Tokyo 1040045, Japan

[2] Toyama Univ, Dept Internal Med 3, Toyama 930, Japan

[3] Chugoku Canc Ctr, Natl Hosp Org Kure Med Ctr, Inst Clin Res, Hiroshima, Japan

[4] Chugoku Canc Ctr, Natl Hosp Org Kure Med Ctr, Dept Surg, Hiroshima, Japan

[5] Wakayama Med Univ, Dept Internal Med 2, Wakayama, Japan

[6] Aichi Canc Ctr Res Inst, Div Oncol Pathol, Nagoya, Aichi, Japan

[7] Aichi Canc Ctr Hosp, Dept Gastroenterol Surg, Nagoya, Aichi 464, Japan

来源：

ONCOGENE | 2013年 / 32卷 / 17期

关键词：

field for cancerization; chromosome X; DNA methylation; gastrointestinal cancer; Helicobacter pylori; ABERRANT DNA METHYLATION; SQUAMOUS-CELL CARCINOMA; GASTRIC MUCOSAE; HELICOBACTER-PYLORI; SILENCED GENES; CANCER; HYPERMETHYLATION; EXPRESSION; BREAST; RISK;

D O I：

10.1038/onc.2012.228

中图分类号：

Q5 [生物化学]; Q7 [分子生物学];

学科分类号：

071010 ; 081704 ;

摘要：

Tumor-suppressor genes on chromosome X can be inactivated by a single hit, any of the point mutations, chromosomal loss and aberrant DNA methylation. As aberrant DNA methylation can be induced frequently, we here aimed to identify a tumor-suppressor gene on chromosome X inactivated by promoter DNA methylation. Of 69 genes on chromosome X upregulated by treatment of a gastric cancer cell line with a DNA-demethylating agent, 5-aza-2'-deoxycytidine, 11 genes had low or no expression in the cell line and abundant expression in normal gastric mucosae. Among them, FHL1 was frequently methylation-silenced in gastric and colon cancer cell lines, and methylated in primary gastric (21/80) and colon (5/50) cancers. Knockdown of the endogenous FHL1 in two cell lines by two kinds of shRNAs significantly increased cell growth in vitro and sizes of xenografts in nude mice. Expression of exogenous FHL1 in a non-expressing cell line significantly reduced its migration, invasion and growth. Notably, a somatic mutation (G642T; Lys214Asn) was identified in one of 144 colon cancer specimens, and the mutant FHL1 was shown to lack its inhibitory effects on migration, invasion and growth. FHL1 methylation was associated with Helicobacter pylori infection and accumulated in normal-appearing gastric mucosae of gastric cancer patients. These data showed that FHL1 is a methylation-silenced tumor-suppressor gene on chromosome X in gastrointestinal cancers, and that its silencing contributes to the formation of an epigenetic field for cancerization. Oncogene (2013) 32, 2140-2149; doi:10.1038/onc.2012.228; published online 11 June 2012

引用

页码：2140 / 2149

页数：10

共 43 条

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