JIB-04, a Pan-Inhibitor of Histone Demethylases, Targets Histone-Lysine-Demethylase-Dependent AKT Pathway, Leading to Cell Cycle Arrest and Inhibition of Cancer Stem-Like Cell Properties in Hepatocellular Carcinoma Cells.

JIB-04, a pan-histone lysine demethylase (KDM) inhibitor, targets drug-resistant cells, along with colorectal cancer stem cells (CSCs), which are crucial for cancer recurrence and metastasis. Despite the advances in CSC biology, the effect of JIB-04 on liver CSCs (LCSCs) and the malignancy of hepatocellular carcinoma (HCC) has not been elucidated yet. Here, we showed that JIB-04 targeted KDMs, leading to the growth inhibition and cell cycle arrest of HCC, and abolished the viability of LCSCs. JIB-04 significantly attenuated CSC tumorsphere formation, growth, relapse, migration, and invasion in vitro. Among KDMs, the deficiency of KDM4B, KDM4D, and KDM6B reduced the viability of the tumorspheres, suggesting their roles in the function of LCSCs. RNA sequencing revealed that JIB-04 affected various cancer-related pathways, especially the PI3K/AKT pathway, which is crucial for HCC malignancy and the maintenance of LCSCs. Our results revealed KDM6B-dependent AKT2 expression and the downregulation of E2F-regulated genes via JIB-04-induced inhibition of the AKT2/FOXO3a/p21/RB axis. A ChIP assay demonstrated JIB-04-induced reduction in H3K27me3 at the AKT2 promoter and the enrichment of KDM6B within this promoter. Overall, our results strongly suggest that the inhibitory effect of JIB-04 on HCC malignancy and the maintenance of LCSCs is mediated via targeting the KDM6B-AKT2 pathway, indicating the therapeutic potential of JIB-04.

Health Behaviors of Korean Gastric Cancer Survivors with Hypertension: A Propensity Analysis of KNHANES III-V (2005-2012).

OBJECTIVE: This study provides a comparison of health behaviors between gastric cancer survivors with hypertension and non-cancer subjects in Korea. METHODS: Data from the Korean National Health and Nutrition Examination Survey (KNHANES) for the period of 2005-2012 were used in this study. A propensity score matching method was used to compare health behaviors. Before the matching of propensity scores, the number of participants was 11034 (102 gastric cancer survivors and 10932 non-cancer participants). A 1:5 propensity score matching procedure yielded a total of 480 participants (80 gastric cancer survivors and 400 non-cancer participants) for the final analysis. Drinking, smoking, physical activity, antihypertensive medication adherence, self-reported diet control, and sodium intake accordance in the two groups were compared. A complex samples logistic regression analysis was conducted to assess any differences between the two groups. RESULTS: The group of hypertensive gastric cancer survivors had lower alcohol consumption (OR = 0.30; 95% CI: 0.14-0.66; p-value = 0.003). They were more likely to be on dietary control than the control group (OR = 3.12; 95% CI: 1.60-6.10; p-value = 0.001). However, there was no significant (p > 0.05) difference in sodium intake accordance or other health behaviors (including medication adherence, smoking, and physical activity) between the two groups. CONCLUSIONS: Our results revealed that gastric cancer survivors with hypertension were more likely to be on dietary control with lower alcohol consumption than the control group. However, there was no significant difference in sodium intake accordance or other health behaviors between the two groups. Therefore, primary care physicians should inform cancer survivors about the appropriate health behaviors to reduce their risk of cardiovascular disease and improve their overall survival rate, even though they say they have been doing health behaviors.

Health Behaviors of Breast Cancer Survivors with Hypertension: A Propensity Analysis of KNHANES III-V (2005-2012).

OBJECTIVE: This study examines health behaviors of breast cancer survivors with hypertension and compares them with those of non-cancer individuals with hypertension. METHODS: In this cross-sectional study, a total of 10,996 hypertensive adults (≥ 19 years) who participated in the 2005-2012 Korean National Health and Nutrition Examination Survey (KNHANES) were considered. Data on alcohol consumption, smoking, physical activity, antihypertensive medication adherence, self-reported diet control, and sodium intake were collected through self-report questionnaire. A total of 64 breast cancer survivors with hypertension and 10,932 non-cancer participants with hypertension were identified. To better compare health behaviors of the two groups, 56 breast cancer survivors and 280 non-cancer participants were selected through the 1:5 nearest available matching based on estimated propensity scores. Multivariate analysis was conducted to determine any differences between the two groups. RESULTS: According to multivariate analysis, breast cancer survivors with hypertension (n = 56) were significantly less likely to consume alcohol (odds ratio (OR): 3.75; 95% confidence interval (CI): 1.06-13.29) but significantly more likely to have sodium intake of more than 2400 mg (OR: 2.98; 95% CI: 1.27-6.97) than the propensity-matched control group (n = 280). There was no significant difference in other health behaviors between the two groups. CONCLUSIONS: Breast cancer survivors require active interventions for healthy behaviors related to the management of comorbid conditions such as hypertension to reduce the risk of cardiovascular disease and improve their overall survival rate.