The crosstalk between the RNA demethylase, non‐coding RNAs, and transcription factors in gastric cancer: An ALKBH5 perspective

Clinical and Translational Discovery, Journal Year: 2023, Volume and Issue: 3(2)

Published: April 1, 2023

Gastric cancer (GC) is the fifth most frequently diagnosed worldwide and one of leading causes cancer-related deaths.1 Over million (1 089 103) new cases GC were in 2020, which led to 768 793 deaths.2 The molecular classification complicated but well-articulated. applied histopathological was proposed by P. Lauren with three main subtypes: intestinal, diffuse, mixed.3 Cancer Genome Atlas research network has identified four subtypes characteristic abnormalities: Epstein-Barr virus positive, microsatellite instability-high, genomically stable, tumors chromosomal instability.4 Treatments for are comparatively inclusive effective.2 Although extensive mechanisms have been elucidated biological processes prognosis, there still challenges diagnosis treatment due unclearness multifarious participators involved progression. Recent advances genomics transcriptomics provided insights into aberrantly activated pathways GC. In recently published article Clinical Translational Medicine, Fang et al. demonstrated that existence ALKBH5, an RNA demethylase known play a crucial role regulation stability metabolism,5 accelerates progression stabilizing JAK1 mRNA thus activating oncogenic JAK1-STAT3 pathway. Meanwhile, LINC00659 initialed m6 modification function ALKBH5 YTHDF2-dependent manner.6 N6-methyladenosine (m6A) highly pervasive mRNAs noncoding RNAs affects splicing, translation, stability, epigenetic modification.7 It universally acknowledged m6A methylation modulated series modulator enzymes termed “writers” (methyltransferase), “erasers” (demethylases), “readers” (proteins). (AlkB Homolog 5, Demethylase) belongs Fe (II)/α-ketoglutarate-dependent dioxygenase family, employs ferrous iron oxygen eliminate aliphatic hydrocarbons or heteroatom groups from diverse substrates, such as DNA, RNA, proteins.8 As demethylase, catalyzes process erasure, essential post-transcriptional regulatory eukaryotic mRNAs.9 Due effects canonical oncogenes, recognized significant regulator gastrointestinal carcinogenesis (Table 1). predominant functions include cellular responses hypoxia, expression transcription factors non-coding RNAs, aberrant modifications.5 To add up, ALKBH5-PD-L1-regulating axis promote immune evasion intrahepatic cholangiocarcinoma inhibiting expansion cytotoxicity T cells.10 Fang's work highlighted on leads activation pathway, gastric carcinogenesis. also comprehensive landscape where both long (lncRNA) reader protein contributed cooperatively ALKBH5. Along blooming transcriptome analysis, lncRNAs emerged nonnegligible their regulating gene processes. described lncRNA implicated mainly colorectal (CRC). Studies revealed generated cancer-associated fibroblasts then transferred cells via exosomes. Functional assays proved its promoting CRC cell proliferation, invasion, migration, epithelial-mesenchymal transition miR-342-3p/ANXA2 axis.26 YTHDF2 noteworthy proven be overexpressed tissues lines metabolism translation. Functionally speaking, knockdown could dramatically inhibit invasion cells.27 But mechanism tumor-promoting remains inconclusive. work, found responsible formation complex, required binding mRNA. And indispensable maintaining stability. These findings enriched two newly crystal structure pattern m6A-containing ssRNA identified, enables receptor-based rational drug design approaches selective inhibitors.28 fact, several small molecules effective another more studied demethylases, fat mass obesity-associated protein. Several studies presented cofactor 2-oxoglutarate (2OG) analogs, like N-oxalylglycine29 succinate30 inhibitors, since demethylation activity requires 2OG. ability patterns these inhibitors confirmed X-ray crystallography enzyme kinetics studies, concerns about need resolved. Firstly, it vital gain thorough understanding underlying heterogeneous downstream effectors various types avoid potential side effects, especially when works tumor suppressor ALKBH5.13, 22 currently available discovered limited pre-clinical assays. Comprehensive trials pharmacokinetic characteristics latent off-target await conducted before further clinical applications. authors acknowledge technical support Core Utilities Genomics Pathobiology Department Anatomical Cellular Pathology, Chinese University Hong Kong. This supported National Natural Science Foundation China, Grant Number: 82272990. declare no conflict interest.

Language: Английский

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Gastroenterology, Journal Year: 2023, Volume and Issue: 165(6), P. 1581 - 1582

Published: Sept. 19, 2023

Language: Английский

Epigenetic and Posttranslational Regulation of Ferroptosis

Springer eBooks, Journal Year: 2023, Volume and Issue: unknown, P. 383 - 403

Published: Jan. 1, 2023

Language: Английский