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.

Enhancer Remodeling and MicroRNA Alterations Are Associated with Acquired Resistance to ALK Inhibitors

Yun, Mi Ran,Lim, Sun Min,Kim, Seon-Kyu,Choi, Hun Mi,Pyo, Kyoung-Ho,Kim, Seong Keun,Lee, Ji Min,Lee, You Won,Choi, Jae Woo,Kim, Hye Ryun,Hong, Min Hee,Haam, Keeok,Huh, Nanhyung,Kim, Jong-Hwan,Kim, Yong American Association for Cancer Research 2018 Cancer research Vol.78 No.12

<P>Epigenetic deregulation drives acquired resistance to ALK inhibitors in ALK-positive lung cancer.</P><P>Anaplastic lymphoma kinase (ALK) inhibitors are highly effective in patients with <I>ALK</I> fusion–positive lung cancer, but acquired resistance invariably emerges. Identification of secondary mutations has received considerable attention, but most cases cannot be explained by genetic causes alone, raising the possibility of epigenetic mechanisms in acquired drug resistance. Here, we investigated the dynamic changes in the transcriptome and enhancer landscape during development of acquired resistance to ALK inhibitors. Histone H3 lysine 27 acetylation (H3K27ac) was profoundly altered during acquisition of resistance, and enhancer remodeling induced expression changes in both miRNAs and mRNAs. Decreased H3K27ac levels and reduced miR-34a expression associated with the activation of target genes such as AXL. Panobinostat, a pan-histone deacetylase inhibitor, altered the H3K27ac profile and activated tumor-suppressor miRNAs such as miR-449, another member of the miR-34 family, and synergistically induced antiproliferative effects with ALK inhibitors on resistant cells, xenografts, and <I>EML4-ALK</I> transgenic mice. Paired analysis of patient samples before and after treatment with ALK inhibitors revealed that repression of miR-34a or miR-449a and activation of AXL were mutually exclusive of secondary mutations in ALK. Our findings indicate that enhancer remodeling and altered expression of miRNAs play key roles in cancer drug resistance and suggest that strategies targeting epigenetic pathways represent a potentially effective method for overcoming acquired resistance to cancer therapy.</P><P><B>Significance:</B> Epigenetic deregulation drives acquired resistance to ALK inhibitors in ALK-positive lung cancer. <I>Cancer Res; 78(12); 3350–62. ©2018 AACR</I>.</P>

Sex Difference in the Association between Serum Homocysteine Level and Non-Alcoholic Fatty Liver Disease

Bo-Youn Won,Kyung-Chae Park,Soo-Hyun Lee,Sung-Hwan Yun,Moon-Jong Kim,Kye-Seon Park,Young-Sang Kim,Ji-Hee Haam,Hyung-Yuk Kim,Hye-Jung Kim,Ki-Hyun Park 대한가정의학회 2016 Korean Journal of Family Medicine Vol.37 No.4

Background: The relationship between serum homocysteine levels and non-alcoholic fatty liver disease is poorly understood. This study aims to investigate the sex-specific relationship between serum homocysteine level and non-alcoholic fatty liver disease in the Korean population. Methods: This cross-sectional study included 150 men and 132 women who participated in medical examination programs in Korea from January 2014 to December 2014. Patients were screened for fatty liver by abdominal ultrasound and patient blood samples were collected to measure homocysteine levels. Patients that consumed more than 20 grams of alcohol per day were excluded from this study. Results: The homocysteine level (11.56 vs. 8.05 nmol/L) and the proportion of non-alcoholic fatty liver disease (60.7% vs. 19.7%) were significantly higher in men than in women. In men, elevated serum homocysteine levels were associated with a greater prevalence of non-alcoholic fatty liver disease (quartile 1, 43.6%; quartile 4, 80.6%; P=0.01); however, in females, there was no significant association between serum homocysteine levels and the prevalence of non-alcoholic fatty liver disease. In the logistic regression model adjusted for age and potential confounding parameters, the odds ratio for men was significantly higher in the uppermost quartile (model 3, quartile 4: odds ratio, 6.78; 95% confidential interval, 1.67 to 27.56); however, serum homocysteine levels in women were not associated with non-alcoholic fatty liver disease in the crude model or in models adjusted for confounders. Conclusion: Serum homocysteine levels were associated with the prevalence of non-alcoholic fatty liver disease in men.

Low levels of total and high-molecular-weight adiponectin may predict non-alcoholic fatty liver in Korean adults

Kim, Young-Sang,Lee, Soo-Hyun,Park, Seung Geon,Won, Bo Youn,Chun, Hyejin,Cho, Doo-Yeoun,Kim, Moon-Jong,Lee, Ji Eun,Haam, Ji-Hee,Han, Kunhee Elsevier 2020 clinical and experimental Vol.103 No.-

<P><B>Abstract</B></P> <P><B>Objectives</B></P> <P>While weight gain is known as a predictor of non-alcoholic fatty liver disease (NAFLD) incidence, it remains controversial whether adipokine levels predict the development of NAFLD. We aimed to investigate the relationship of total adiponectin, high-molecular-weight (HMW) adiponectin, and leptin with the development and improvement of non-alcoholic fatty liver (NAFL) independent of sex and weight change over a maximum of 8.5 years.</P> <P><B>Methods</B></P> <P>This prospective study enrolled 2735 participants in a hospital health check-up setting. Adipokine levels were measured at baseline. NAFL was assessed with liver ultrasonography, and the development or improvement of NAFL was determined by repeated ultrasonography at follow-ups.</P> <P><B>Results</B></P> <P>Cross-sectional analyses revealed that total and HMW adiponectin levels were inversely associated with NAFL prevalence. In longitudinal analyses, the incidence of NAFL was 5.6 per 100-person-years during the observation period. The hazard ratios (HRs) per 1 μg/mL increase in the levels of total and HMW adiponectin were 0.900 (0.836–0.969) and 0.846 (0.754–0.948), respectively. Sex-stratified analyses showed that total and HMW adiponectin levels were significantly related to NAFL incidence only in women. In the subgroup of minimal weight change, only HMW adiponectin was a significant predictor for NAFL. Leptin predicted NAFL in the subgroup with weight gain. The improvement of NAFL was influenced by weight change, but not by adipokine levels.</P> <P><B>Conclusions</B></P> <P>Low levels of total and HMW adiponectin may predict the development of NAFL independent of pathophysiological factors including obesity and insulin resistance. This predictability was evident in women. Leptin was a significant predictor for NAFL in the subjects with weight gain.</P> <P><B>Highlights</B></P> <P> <UL> <LI> Low levels of total and HMW adiponectin may predict the development of NAFL. </LI> <LI> Sex difference exists in the relationship between adiponectin and NAFL incidence. </LI> <LI> Leptin may be a significant predictor for NAFL in the subjects with weight gain. </LI> <LI> Weight reduction, but not adipokines, is associated with the improvement of NAFL. </LI> </UL> </P>