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

• Published in: Oncogene Vol. 32; no. 17; pp. 2140 - 2149
• Main Authors: Asada, K, Ando, T, Niwa, T, Nanjo, S, Watanabe, N, Okochi-Takada, E, Yoshida, T, Miyamoto, K, Enomoto, S, Ichinose, M, Tsukamoto, T, Ito, S, Tatematsu, M, Sugiyama, T, Ushijima, T
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 25.04.2013; Nature Publishing Group
• Subjects: 631/208/2489/2487/2486; 631/67/1504/1829; 631/67/581; 692/699/255/1918; Adult; Aged; Aged, 80 and over; Animals; Apoptosis; Base Sequence; Cell Biology; Chromosomes; Colon cancer; Colonic Neoplasms - genetics; Colonic Neoplasms - metabolism; Colorectal cancer; CpG Islands; DNA Methylation; DNA Mutational Analysis; Epigenesis, Genetic; Epigenetics; Female; Gastric cancer; Gastric Mucosa - metabolism; Gene mutations; Gene Silencing; Genes; Genes, Tumor Suppressor; Genetic aspects; HCT116 Cells; Health aspects; Helicobacter pylori; Human Genetics; Humans; Internal Medicine; Intracellular Signaling Peptides and Proteins - genetics; LIM Domain Proteins - genetics; Male; Medicine; Medicine & Public Health; Mice; Mice, Inbred BALB C; Mice, Nude; Middle Aged; Muscle Proteins - genetics; Mutation; Neoplasm Transplantation; Oncology; original-article; Physiological aspects; Promoter Regions, Genetic; Risk factors; Stomach cancer; Stomach Neoplasms - genetics; Stomach Neoplasms - metabolism; Tumor cell lines; Tumor suppressor genes; Tumors; X Chromosome; Xenografts; Japan; DNA methylation; chromosome X; gastrointestinal cancer; field for cancerization
• ISSN: 0950-9232; 1476-5594
• DOI: 10.1038/onc.2012.228

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.