Wdr5-mediated H3K4me3 coordinately regulates cell differentiation, proliferation termination, and survival in digestive organogenesis.

Food digestion requires the cooperation of different digestive organs. The differentiation of digestive organs is crucial for larvae to start feeding. Therefore, during digestive organogenesis, cell identity and the tissue morphogenesis must be tightly coordinated but how this is accomplished is poorly understood. Here, we demonstrate that WD repeat domain 5 (Wdr5)-mediated H3K4 tri-methylation (H3K4me3) coordinately regulates cell differentiation, proliferation and apoptosis in zebrafish organogenesis of three major digestive organs including intestine, liver, and exocrine pancreas. During zebrafish digestive organogenesis, some of cells in these organ primordia usually undergo differentiation without apoptotic activity and gradually reduce their proliferation capacity. In contrast, cells in the three digestive organs of wdr5-/- mutant embryos retain progenitor-like status with high proliferation rates, and undergo apoptosis. Wdr5 is a core member of COMPASS complex to implement H3K4me3 and its expression is enriched in digestive organs from 2 days post-fertilization (dpf). Further analysis reveals that lack of differentiation gene expression is due to significant decreases of H3K4me3 around the transcriptional start sites of these genes; this histone modification also reduces the proliferation capacity in differentiated cells by increasing the expression of apc to promote the degradation of ß-Catenin; in addition, H3K4me3 promotes the expression of anti-apoptotic genes such as xiap-like, which modulates p53 activity to guarantee differentiated cell survival. Thus, our findings have discovered a common molecular mechanism for cell fate determination in different digestive organs during organogenesis, and also provided insights to understand mechanistic basis of human diseases in these digestive organs.

Amentoflavone attenuates cell proliferation and induces ferroptosis in human gastric cancer by miR-496/ATF2 axis.

Amentoflavone (AF) is a natural multifunctional biflavonoid that has been revealed to possess multiple biological activities, including anticancer activity. Here, this work focused on exploring the functions and mechanism of AF in gastric cancer (GC). Levels of genes and proteins were examined by quantitative real-time PCR and western blotting. Cell proliferation and cell death were analyzed using cell counting kit-8, colony formation, and lactate dehydrogenase (LDH) release assay, respectively. Cell ferroptosis was evaluated by detecting the levels of malondialdehyde (MDA), reduced glutathione (GSH), Fe2+ , and intracellular reactive oxygen species (ROS). The binding between miR-496 and activating transcription factor 2 (ATF2) was confirmed by using dual-luciferase reporter assay. Murine xenograft assay was conducted for in vivo experiments. The results showed that AF suppressed the proliferation and induced ferroptotic cell death in GC cells. MiR-496 expression was decreased in GC tissues and cells, and AF treatment increased miR-496 expression level in GC cells. Functionally, miR-496 inhibition reversed the inhibitory effects of AF on GC cell proliferation and promoting effects on ferroptotic cell death. Mechanistically, ATF2 was targeted by miR-496. ATF2 expression was increased in GC tissues and cells, which was decreased by AF treatment and subsequently rescued by miR-496 downregulation in GC cells. Moreover, miR-496 overexpression suppressed the proliferation and induced ferroptotic cell death in GC cells via targeting ATF2. In all, AF suppressed the proliferation and induced ferroptotic cell death in GC cells via miR-496/ATF2 axis, indicating a novel therapeutic approach for GC patients.

LINC01436 Inhibited miR-585-3p Expression and Upregulated MAPK1 Expression to Promote Gastric Cancer Progression.

BACKGROUND: Gastric cancer (GC) is a prevalent type of digestion system malignancies. Dysregulation of long non-coding RNAs (lncRNAs) has been proven to be prognostic factors and biological regulators in human cancers. AIMS: The current study aimed to explore the role of long intergenic non-protein coding RNA 1436 (LINC01436) and its underlying mechanism in the progression of GC. METHODS: RT-qPCR was conducted to measure RNA expression. Western blot was used for exploration of protein level. CCK-8, caspase-3 activity, and transwell assays were applied to evaluate the proliferative, apoptotic, and migratory abilities of GC cells, respectively. Mechanical experiments were used to probe the molecular interplay between genes. RESULTS: High LINC01436 level suggested low overall survival in GC patients, and LINC01436 was highly expressed in GC tissues and cells. Besides, LINC01436 knockdown hampered cell proliferation and migration, while facilitated cell apoptosis. Mechanistically, LINC01436 upregulated mitogen-activated protein kinase 1 (MAPK1) expression by competitively binding with miR-585-3p and inhibiting miR-585-3p expression. Furthermore, LINC01436 negatively regulated miR-585-3p expression by enhancing the zeste 2 polycomb repressive complex 2 subunit (EZH2)-induced trimethylation of histone H3 at lysine 27 (H3K27me3) on miR-585-3p promoter. Final rescue assays revealed that overexpression of MAPK1 could rescue the suppressive influence of LINC01436 depletion on GC progression. CONCLUSIONS: LINC01436 epigenetically silences miR-585-3p and acts as miR-585-3p to upregulate MAPK1 expression and promote GC progression.

LncRNA NKILA correlates with the malignant status and serves as a tumor-suppressive role in rectal cancer.

NF-κB interacting lncRNA (NKILA) has been found to function as a tumor-suppressive role in various human cancers. However, the role of NKILA in rectal cancer is still unknown. The objective of this study is to investigate the clinical value and biological function of NKILA in rectal cancer. The association between NKILA expression and clinical variables including prognosis was estimated in rectal cancer patients. The gain-of-function study of NKILA in rectal cancer cell was conducted to evaluate the effect of NKILA on cell proliferation, migration, invasion, and NF-κB signaling pathway. The results suggested NKILA expression was decreased in rectal cancer tissues and cells, and correlated with clinical stage, T classification, N classification and M classification. NKILA low-expression was an independent poor prognostic factor in rectal cancer patients. NKILA-inhibited rectal cancer cell proliferation, migration, and invasion via suppressing NF-κB signaling. In conclusion, NKILA serves as an antioncogenic lncRNA in rectal cancer.