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Epigenetic Field for Cancerization
Ushijima, Toshikazu Korean Society for Biochemistry and Molecular Biol 2007 Journal of biochemistry and molecular biology Vol.40 No.2
Epigenetic alterations, represented by aberrant DNA methylation, are deeply involved in human cancers. In gastric cancers, tumor-suppressor genes are inactivated more frequently by promoter methylation than by mutations. We recently showed that H. pylori infection, a potent gastric carcinogenic factor, induces methylation of specific genes in the gastric mucosae. When the methylation levels were analyzed in the gastric mucosae of healthy volunteers, cases with a single gastric cancer, and cases with multiple gastric cancers, who have increasing levels of risks for gastric cancers, there was a significant increasing trend in the methylation levels among the individuals without current H. pylori infection. This finding unequivocally showed the presence of an epigenetic field for cancerization. The degree of the field defect was measured more conveniently using methylation levels of marker genes than using those of tumor-suppressor genes. The presence of an epigenetic field for cancerization has been indicated for liver, colon, Barrett's esophageal, lung, breast, and renal cancers. Since decreased transcription is involved in the specificity of methylated genes, it is likely that specific genes are methylated according to carcinogenic factors. These findings emphasize the usefulness of DNA methylation as a marker for past exposure to carcinogens and future risk of cancer development.
Takeshima, Hideyuki,Ikegami, Daigo,Wakabayashi, Mika,Niwa, Tohru,Kim, Young-Joon,Ushijima, Toshikazu IRL Press] ; Oxford University Press 2012 Carcinogenesis Vol.33 No.12
<P>A field for cancerization (field defect), where genetic and epigenetic alterations are accumulated in normal-appearing tissues, is involved in human carcinogenesis, especially cancers associated with chronic inflammation. Although aberrant DNA methylation is involved in the field defect and induced by chronic inflammation, it is still unclear for trimethylation of histone H3 lysine 27 (H3K27me3), which is involved in gene repression independent of DNA methylation and functions as a pre-mark for aberrant DNA methylation. In this study, using a mouse colitis model induced by dextran sulfate sodium (DSS), we aimed to clarify whether aberrant H3K27me3 is induced by inflammation and involved in a field defect. ChIP-on-chip analysis of colonic epithelial cells revealed that H3K27me3 levels were increased or decreased for 266 genomic regions by aging, and more extensively (23 increased and 3574 decreased regions) by colitis. Such increase or decrease of H3K27me3 was induced as early as 2 weeks after the initiation of DSS treatment, and persisted at least for 16 weeks even after the inflammation disappeared. Some of the aberrant H3K27me3 in colonic epithelial cells was carried over into colon tumors. Furthermore, H3K27me3 acquired at Dapk1 by colitis was followed by increased DNA methylation, supporting its function as a pre-mark for aberrant DNA methylation. These results demonstrated that aberrant H3K27me3 can be induced by exposure to a specific environment, such as colitis, and suggested that aberrant histone modification, in addition to aberrant DNA methylation, is involved in the formation of a field defect.</P>
Causal relationship between the loss of RUNX3 expression and gastric cancer
Qing-Lin Li,Chohei Sakakura,Kosei Ito,Xin-Zi Chi,Lee, Kwang-Youl,Lee, Chang-Woo,Han, Sang-Bae,Kim, Hwan-Mook,Kim, Wun-Jae,Atsushi Kaneda,Toshikazu Ushijima,Yoshiaki Ito,Bae, Suk-Chul 이화여자대학교 세포신호전달연구센터 2002 고사리 세포신호전달 심포지움 Vol. No.4
The human runt-related gene RUNX3/PEBP2αC, located on chromosome 1p36, is a major mediator of signals elicited by members of the transforming growth factor-β(TGF-β) superfamily. Here we show that 45-60% of gastric cancer cell lines and surgically resected specimens do not significantly express RUNX3 due to a combination of hemizygous deletion and hypermethylation of the RUNX3 promoter region. Tumorigenicity of gastric cancer cell lines in nude mice was inversely related to their level of RUNX3 expression, and one gastric tumor associated mutation(R122C), occurring within the conserved Runt domain completely abolished the tumor suppressive effect of RUNX3. The results suggest that a lack of RUNX3 function is causally related to the genesis and progression of human gastric cancer.
Chi, Xin-Zi,Yang, Jeung-Ook,Lee, Kwang-Youl,Ito, Kosei,Sakakura, Chohei,Li, Qing-Lin,Kim, Hye-Ryun,Cha, Eun-Jeung,Lee, Yong-Hee,Kaneda, Atsushi,Ushijima, Toshikazu,Kim, Wun-Jae,Ito, Yoshiaki,Bae, Suk- American Society for Microbiology 2005 Molecular and cellular biology Vol.25 No.18
<B>ABSTRACT</B><P><I>RUNX3</I> has been suggested to be a tumor suppressor of gastric cancer. The gastric mucosa of the <I>Runx3</I>-null mouse develops hyperplasia due to enhanced proliferation and suppressed apoptosis accompanied by a decreased sensitivity to transforming growth factor β1 (TGF-β1). It is known that TGF-β1 induces cell growth arrest by activating <I>CDKN1A</I> (<I>p21</I><SUP><I>WAF1</I></SUP><SUP>/<I>Cip1</I></SUP>), which encodes a cyclin-dependent kinase inhibitor, and this signaling cascade is considered to be a tumor suppressor pathway. However, the lineage-specific transcription factor that cooperates with SMADs to induce <I>p21</I> expression is not known. Here we show that <I>RUNX3</I> is required for the TGF-β-dependent induction of <I>p21</I> expression in stomach epithelial cells. Overexpression of <I>RUNX3</I> potentiates TGF-β-dependent endogenous <I>p21</I> induction. In cooperation with SMADs, RUNX3 synergistically activates the <I>p21</I> promoter. In contrast, <I>RUNX3</I>-<I>R122C</I>, a mutation identified in a gastric cancer patient, abolished the ability to activate the <I>p21</I> promoter or cooperate with SMADs. Furthermore, areas in mouse and human gastric epithelium where <I>RUNX3</I> is expressed coincided with those where <I>p21</I> is expressed. Our results suggest that at least part of the tumor suppressor activity of <I>RUNX3</I> is associated with its ability to induce <I>p21</I> expression.</P>