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.

Assessment of liver fibrosis severity using computed tomography-based liver and spleen volumetric indices in patients with chronic liver disease.

OBJECTIVES: To evaluate whether the liver and spleen volumetric indices, measured on portal venous phase CT images, could be used to assess liver fibrosis severity in chronic liver disease. METHODS: From 2007 to 2017, 558 patients (mean age 48.7 ± 13.1 years; 284 men and 274 women) with chronic liver disease (n = 513) or healthy liver (n = 45) were retrospectively enrolled. The liver volume (sVolL) and spleen volume (sVolS), normalized to body surface area and liver-to-spleen volume ratio (VolL/VolS), were measured on CT images using a deep learning algorithm. The correlation between the volumetric indices and the pathologic liver fibrosis stages combined with the presence of decompensation (F0, F1, F2, F3, F4C [compensated cirrhosis], and F4D [decompensated cirrhosis]) were assessed using Spearman's correlation coefficient. The performance of the volumetric indices in the diagnosis of advanced fibrosis, cirrhosis, and decompensated cirrhosis were evaluated using the area under the receiver operating characteristic curve (AUC). RESULTS: The sVolS (ρ = 0.47-0.73; p < .001) and VolL/VolS (ρ = -0.77-- 0.48; p < .001) showed significant correlation with liver fibrosis stage in all etiological subgroups (i.e., viral hepatitis, alcoholic and non-alcoholic fatty liver, and autoimmune diseases), while the significant correlation of sVolL was noted only in the viral hepatitis subgroup (ρ = - 0.55; p < .001). To diagnose advanced fibrosis, cirrhosis, and decompensated cirrhosis, the VolL/VolS (AUC 0.82-0.88) and sVolS (AUC 0.82-0.87) significantly outperformed the sVolL (AUC 0.63-0.72; p < .001). CONCLUSION: The VolL/VolS and sVolS may be used for assessing liver fibrosis severity in chronic liver disease. KEY POINTS: • Volumetric indices of liver and spleen measured on computed tomography images may allow liver fibrosis severity to be assessed in patients with chronic liver disease.

SETD5 regulates the OGT-catalyzed O-GlcNAcylation of RNA polymerase II, which is involved in the stemness of colorectal cancer cells.

The dosage-dependent recruitment of RNA polymerase II (Pol II) at the promoters of genes related to neurodevelopment and stem cell maintenance is required for transcription by the fine-tuned expression of SET-domain-containing protein 5 (SETD5). Pol II O-GlcNAcylation by O-GlcNAc transferase (OGT) is critical for preinitiation complex formation and transcription cycling. SETD5 dysregulation has been linked to stem cell-like properties in some cancer types; however, the role of SETD5 in cancer cell stemness has not yet been determined. We here show that aberrant SETD5 overexpression induces stemness in colorectal cancer (CRC) cells. SETD5 overexpression causes the upregulation of PI3K-AKT pathway-related genes and cancer stem cell (CSC) markers such as CD133, Kruppel-like factor 4 (KLF4), and estrogen-related receptor beta (ESRRB), leading to the gain of stem cell-like phenotypes. Our findings also revealed a functional relationship between SETD5, OGT, and Pol II. OGT-catalyzed Pol II glycosylation depends on SETD5, and the SETD5-Pol II interaction weakens in OGT-depleted cells, suggesting a SETD5-OGT-Pol II interdependence. SETD5 deficiency reduces Pol II occupancy at PI3K-AKT pathway-related genes and CD133 promoters, suggesting a role for SETD5-mediated Pol II recruitment in gene regulation. Moreover, the SETD5 depletion nullified the SETD5-induced stemness of CRC cells and Pol II O-GlcNAcylation. These findings support the hypothesis that SETD5 mediates OGT-catalyzed O-GlcNAcylation of RNA Pol II, which is involved in cancer cell stemness gain via CSC marker gene upregulation.

Development and Validation of a Simple Index Based on Non-Enhanced CT and Clinical Factors for Prediction of Non-Alcoholic Fatty Liver Disease.

OBJECTIVE: A widely applicable, non-invasive screening method for non-alcoholic fatty liver disease (NAFLD) is needed. We aimed to develop and validate an index combining computed tomography (CT) and routine clinical data for screening for NAFLD in a large cohort of adults with pathologically proven NAFLD. MATERIALS AND METHODS: This retrospective study included 2218 living liver donors who had undergone liver biopsy and CT within a span of 3 days. Donors were randomized 2:1 into development and test cohorts. CTL-S was measured by subtracting splenic attenuation from hepatic attenuation on non-enhanced CT. Multivariable logistic regression analysis of the development cohort was utilized to develop a clinical-CT index predicting pathologically proven NAFLD. The diagnostic performance was evaluated by analyzing the areas under the receiver operating characteristic curve (AUC). The cutoffs for the clinical-CT index were determined for 90% sensitivity and 90% specificity in the development cohort, and their diagnostic performance was evaluated in the test cohort. RESULTS: The clinical-CT index included CTL-S, body mass index, and aspartate transaminase and triglyceride concentrations. In the test cohort, the clinical-CT index (AUC, 0.81) outperformed CTL-S (0.74; p < 0.001) and clinical indices (0.73-0.75; p < 0.001) in diagnosing NAFLD. A cutoff of ≥ 46 had a sensitivity of 89% and a specificity of 41%, whereas a cutoff of ≥ 56.5 had a sensitivity of 57% and a specificity of 89%. CONCLUSION: The clinical-CT index is more accurate than CTL-S and clinical indices alone for the diagnosis of NAFLD and may be clinically useful in screening for NAFLD.

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.

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.