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Epigenetic Activation of Tensin 4 Promotes Gastric Cancer Progression
Mirang Kim,Haejeong Heo,Hee-Jin Kim,Keeok Haam,Hyun Ahm Sohn,Yang-Ji Shin,Hanyong Go,Hyo-Jung Jung,Jong-Hwan Kim,Sang-Il Lee,Kyu-Sang Song,Min-Ju Kim,Haeseung Lee,Eun-Soo Kwon,Seon-Young Kim,Yong Sung 한국분자세포생물학회 2023 Molecules and cells Vol.46 No.5
Gastric cancer (GC) is a complex disease influenced by multiple genetic and epigenetic factors. Chronic inflammation caused by Helicobacter pylori infection and dietary risk factors can result in the accumulation of aberrant DNA methylation in gastric mucosa, which promotes GC development. Tensin 4 (TNS4), a member of the Tensin family of proteins, is localized to focal adhesion sites, which connect the extracellular matrix and cytoskeletal network. We identified upregulation of TNS4 in GC using quantitative reverse transcription PCR with 174 paired samples of GC tumors and adjacent normal tissues. Transcriptional activation of TNS4 occurred even during the early stage of tumor development. TNS4 depletion in GC cell lines that expressed high to moderate levels of TNS4, i.e., SNU-601, KATO III, and MKN74, reduced cell proliferation and migration, whereas ectopic expression of TNS4 in those lines that expressed lower levels of TNS4, i.e., SNU-638, MKN1, and MKN45 increased colony formation and cell migration. The promoter region of TNS4 was hypomethylated in GC cell lines that showed upregulation of TNS4. We also found a significant negative correlation between TNS4 expression and CpG methylation in 250 GC tumors based on The Cancer Genome Atlas (TCGA) data. This study elucidates the epigenetic mechanism of TNS4 activation and functional roles of TNS4 in GC development and progression and suggests a possible approach for future GC treatments.
Yoon, Byoung-Ha,Kim, Mirang,Kim, Min-Hyeok,Kim, Hee-Jin,Kim, Jeong-Hwan,Kim, Jong Hwan,Kim, Jina,Kim, Yong Sung,Lee, Daeyoup,Kang, Suk-Jo,Kim, Seon-Young Korean Society for Molecular and Cellular Biology 2018 Molecules and cells Vol.41 No.11
The stepwise development of T cells from a multipotent precursor is guided by diverse mechanisms, including interactions among lineage-specific transcription factors (TFs) and epigenetic changes, such as DNA methylation and hydroxymethylation, which play crucial roles in mammalian development and lineage commitment. To elucidate the transcriptional networks and epigenetic mechanisms underlying T-cell lineage commitment, we investigated genome-wide changes in gene expression, DNA methylation and hydroxymethylation among populations representing five successive stages of T-cell development (DN3, DN4, DP, $CD4^+$, and $CD8^+$) by performing RNA-seq, MBD-seq and hMeDIP-seq, respectively. The most significant changes in the transcriptomes and epigenomes occurred during the DN4 to DP transition. During the DP stage, many genes involved in chromatin modification were up-regulated and exhibited dramatic changes in DNA hydroxymethylation. We also observed 436 alternative splicing events, and approximately 57% (252) of these events occurred during the DP stage. Many stage-specific, differentially methylated regions were observed near the stage-specific, differentially expressed genes. The dynamic changes in DNA methylation and hydroxymethylation were associated with the recruitment of stage-specific TFs. We elucidated interactive networks comprising TFs, chromatin modifiers, and DNA methylation and hope that this study provides a framework for the understanding of the molecular networks underlying T-cell lineage commitment.
Kim, Mirang,Park, Young-Kyu,Kang, Tae-Wook,Lee, Sang-Hun,Rhee, Yong-Hee,Park, Jong-Lyul,Kim, Hee-Jin,Lee, Daeyoup,Lee, Doheon,Kim, Seon-Young,Kim, Yong Sung Oxford University Press 2014 Human Molecular Genetics Vol.23 No.3
<P>DNA methylation and hydroxymethylation have been implicated in normal development and differentiation, but our knowledge is limited about the genome-wide distribution of 5-methylcytosine (5 mC) and 5-hydroxymethylcytosine (5 hmC) during cellular differentiation. Using an <I>in vitro</I> model system of gradual differentiation of human embryonic stem (hES) cells into ventral midbrain-type neural precursor cells and terminally into dopamine neurons, we observed dramatic genome-wide changes in 5 mC and 5 hmC patterns during lineage commitment. The 5 hmC pattern was dynamic in promoters, exons and enhancers. DNA hydroxymethylation within the gene body was associated with gene activation. The neurogenesis-related genes <I>NOTCH1</I>, <I>RGMA</I> and <I>AKT1</I> acquired 5 hmC in the gene body and were up-regulated during differentiation. DNA methylation in the promoter was associated with gene repression. The pluripotency-related genes <I>POU5F1</I>, <I>ZFP42</I> and <I>HMGA1</I> acquired 5 mC in their promoters and were down-regulated during differentiation. Promoter methylation also acted as a locking mechanism to maintain gene silencing. The mesoderm development-related genes <I>NKX2-8</I>, <I>TNFSF11</I> and <I>NFATC1</I> acquired promoter methylation during neural differentiation even though they were already silenced in hES cells. Our findings will help elucidate the molecular mechanisms underlying lineage-specific differentiation of pluripotent stem cells during human embryonic development.</P>
Kim, Mirang,Lee, Kyung-Tae,Jang, Hay-Ran,Kim, Jeong-Hwan,Noh, Seung-Moo,Song, Kyu-Sang,Cho, June-Sik,Jeong, Hyun-Yong,Kim, Seon-Young,Yoo, Hyang-Sook,Kim, Yong Sung American Association for Cancer Research 2008 Molecular cancer research Vol.6 No.2
<P>The promoter region of Discoidin, CUB and LCCL domain containing 2 (DCBLD2) was found to be aberrantly methylated in gastric cancer cell lines and in primary gastric cancers, as determined by restriction landmark genomic scanning. DCBLD2 expression was inversely correlated with DCBLD2 methylation in gastric cancer cell lines. Treatment with 5-aza-2'-deoxycytidine and trichostatin A partially reversed DCBLD2 methylation and restored gene expression in DCBLD2-silenced cell lines. In an independent series of 82 paired gastric cancers and adjacent normal tissues, DCBLD2 expression was down-regulated in 79% of gastric cancers as compared with normal tissues as measured by real-time reverse transcription-PCR. Pyrosequencing analysis of the DCBLD2 promoter region revealed abnormal hypermethylation in gastric cancers, and this hypermethylation was significantly correlated with down-regulation of DCBLD2 expression. Furthermore, ectopic expression of DCBLD2 in gastric cancer cell lines inhibited colony formation in both anchorage-dependent and anchorage-independent cultures and also inhibited invasion through the collagen matrix. These data suggest that down-regulation of DCBLD2, often associated with promoter hypermethylation, is a frequent event that may be related to the development of gastric cancer.</P>