N6-methyladenosine (m6A) is a widely investigated RNA modification in studies on the “epigenetic regulation” of mRNAs that is ubiquitously present in eukaryotes. Abnormal changes in m6A levels are closely related to the regulation of RNA metabolism, heat shock stress, tumor occurrence, and development. m6A modifications are catalyzed by the m6A writer complex, which contains RNA methyltransferase-like 3 (METTL3), methyltransferase-like 14 (METTL14), Wilms tumor 1-associated protein (WTAP), and other proteins with methyltransferase (MTase) capability, such as RNA-binding motif protein 15 (RBM15), KIAA1429 and zinc finger CCCH-type containing 13 (ZC3H13). Although METTL3 is the main catalytic subunit, WTAP is a regulatory subunit whose function is to recruit the m6A methyltransferase complex to the target mRNA. Specifically, WTAP is required for the accumulation of METTL3 and METTL14 in nuclear speckles. In this paper, we briefly introduce the molecular mechanism of m6A modification. Then, we focus on WTAP, a component of the m6A methyltransferase complex, and introduce its structure, localization, and physiological functions. Finally, we describe its roles and mechanisms in cancer.
Background N6-methyladenosine (m6A) is a prevalent modification of mRNA and is known to play important roles in tumorigenesis in many types of cancer. The function of N6-methyladenosine (m6A) RNA methylation depends on a variety of methyltransferases and demethylases. AlkB homolog 5 (ALKBH5) is a demethylase, and its biological function has not been completely explored in HCC. Results ALKBH5 is downregulated and has antitumor effects in HCC cells. In addition, Progestin and AdipoQ Receptor 4 (PAQR4) was identified as a downstream target of ALKBH5 based on transcriptome sequencing and validation studies. We found that ALKBH5 decreases PAQR4 mRNA and protein expression in an N6-methyladenosine (m6A)-dependent manner. The study also showed that ALKBH5 changes PAQR4 expression via the m6A reader IGF2BP1. In both in vivo and in vitro experiments, PAQR4 showed a strong association with the development of HCC. Finally, we found that PAQR4 interacts with AKT and enhances PI3K/AKT pathway activation. Conclusions ALKBH5 inhibits HCC growth by downregulating PAQR4 expression in an m6A-dependent manner, therefore suppressing PI3K/AKT pathway activation.
Objective Hepatocellular carcinoma (HCC) is an extremely deadly cancer with few effective therapeutic options available. Ceramide synthases (CERS), a family of enzymes that regulate sphingolipid metabolism, have been suggested to play a role in cancer initiation and progression. Whereas the specific functions of CERS in HCC pathogenesis have not yet been fully elucidated. Methods The TCGA and ICGC databases were employed to analyze the expression levels and clinical relevance of CERS genes in HCC. Functional enrichment analyses were performed to identify pathways and functions associated with CERS5. The correlation between CERS5 and the tumor immune microenvironment was investigated. The mutation landscape and immunotherapy efficacy were evaluated. Functional experiments in vitro were conducted to assess CERS5’s impact on HCC cell proliferation and invasion. Results Aberrant expression of the CERS family was detected not only in HCC but also in other cancers, and has been linked to both overall survival and disease-free survival. Among the CERS family members, CERS5 was identified as the only prognosis-related gene, with up-regulated in HCC validated in the ICGC database and clinical tissue samples. Higher expression levels of CERS5 were associated with a poorer prognosis as well as an advanced pathologic stage and grade, as confirmed by the TCGA and ICGC databases. Besides, a prognostic nomogram combining pathologic stage, tumor status, and the expression of CERS5 was established and further validated, which suggested a favorable value for prognosis prediction. Functional enrichment analyses showed that the overexpression of CERS5 resulted in enriched pathways associated with carcinogenesis, drug metabolism, the PI3K/AKT/mTOR signaling pathway, and cancer immune-related pathways. In addition, the overexpression of CERS5 correlated positively with the expression of genes associated with immunogenic cell death modulators and immune checkpoints, levels of immune cell infiltration, and immunotherapy response, which was featured in an immunologically “hot” environment in the tumor microenvironment. Finally, the functional experiments showed that CERS5 knockdown has been shown to inhibit the growth and invasion of hepatocellular carcinoma, potentially through targeting the PI3K/AKT/mTOR signaling pathway. Conclusions Based on our findings, CERS5 appears to have great potential as both a precise prognostic biomarker and a novel therapeutic target in HCC.
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