BACKGROUND & AIMS: RNA N 6-methyladenosine (m 6 A) modification has recently emerged as a new regulatory mechanism in cancer progression. We aimed to explore the role of the m 6 A regulatory enzyme METTL3 in colorectal cancer (CRC) pathogenesis and its potential as a therapeutic target. METHODS: The expression and clinical implication of METTL3 were investigated in multiple human CRC cohorts. The underlying mechanisms of METTL3 in CRC were investigated by integrative m 6 A sequencing, RNA sequencing, and ribosome profiling analyses. The efficacy of targeting METTL3 in CRC treatment was elucidated in CRC cell lines, patient-derived CRC organoids, and Mettl3-knockout mouse models. RESULTS: Using targeted clustered regularly interspaced short palindromic repeats (CRISPR)/Cas9 dropout screening, we identified METTL3 as the top essential m 6 A regulatory enzyme in CRC. METTL3 was overexpressed in 62.2% (79/127) and 88.0% (44/50) of primary CRCs from 2 independent cohorts. High METTL3 expression predicted poor survival in patients with CRC (n ¼ 374, P < .01). Functionally, silencing METTL3 suppressed tumorigenesis in CRC cells, human-derived primary CRC organoids, and Mettl3-knockout mouse models. We discovered the novel functional m 6 A methyltransferase domain of METTL3 in CRC cells by domain-focused CRISPR screening and mutagenesis assays. Mechanistically, METTL3 directly induced the m 6 A-GLUT1-mTORC1 axis as identified by integrated m 6 A sequencing, RNA sequencing, ribosome sequencing,

Macrophages M1 polarization Hepatocytes Lipid accummulation inflammatory response p38α Steatohepatitis TNFα CXCL10 IL-6 Highlights p38a expression is increased in livers of human patients with non-alcoholic fatty liver diseases. Macrophage p38a induces experimental steatohepatitis. Macrophage p38a causes M1 macrophage polarization. p38a deleted macrophages attenuate steatohepatitic changes in hepatocytes. Pharmacological p38 inhibitors prevent steatohepatitis in mice.

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Non-protein-coding functional elements in the human genome in the postgenomic biology field have been drawing great attention in recent years. Thousands of long non-coding RNAs (lncRNAs) have been found to be expressed in various tumors. Yet only a small proportion of these lncRNAs have been well characterized. We have demonstrated that LINC00460 could affect cell proliferation through epigenetic regulation of KLF2 and CUL4A in human colorectal cancer. However, the clinical significance and biological role of LINC00460 in gastric cancer (GC) remain largely unknown. In this research, we discovered that LINC00460 is remarkably upregulated in GC tissues compared to the non-tumor tissues. Additionally, LINC00460 served as an independent prognostic marker in GC. Functionally, proliferation of GC cells could be regulated by LINC00460 both in vitro and in vivo. RNA sequencing (RNA-seq) analysis for the whole transcriptome indicated that LINC00460 may serve as a key regulatory factor in the tumorigenesis of GC. What's more, the biological function of LINC00460 was mediated, to certain extent, by the direct interaction with enhancer of zeste homolog 2 (EZH2) and lysine (K)specific demethylase 1A (LSD1) proteins. Further analyses indicated that LINC00460 promoted GC proliferation at least partly through the downregulation of tumor suppressor-gene Cyclin G2 (CCNG2), which is mediated by EZH2 and LSD1. In conclusion, our results suggested that LINC00460 acted as an oncogene in GC to inhibit the expression of CCNG2 at least partly by binding with EZH2 and LSD1. Our study could provide additional insights into the development of novel target therapeutic methods for GC.