bims-rimeca 2021-04-25 papers

Biomark Res. 2021 Apr 20. 9(1): 27

Novel insights into the m6A-RNA methyltransferase METTL3 in cancer.

Yiqing Cai, Rui Feng, Tiange Lu, Xiaomin Chen, Xiangxiang Zhou, Xin Wang.

N6-methyladenosine (m6A) is a prevalent internal RNA modification in higher eukaryotic cells. As the pivotal m6A regulator, RNA methyltransferase-like 3 (METTL3) is responsible for methyl group transfer in the progression of m6A modification. This epigenetic regulation contributes to the structure and functional regulation of RNA and further promotes tumorigenesis and tumor progression. Accumulating evidence has illustrated the pivotal roles of METTL3 in a variety of human cancers. Here, we systemically summarize the interaction between METTL3 and RNAs, and illustrate the multiple functions of METTL3 in human cancer. METLL3 is aberrantly expressed in a variety of tumors. Elevation of METTL3 is usually associated with rapid progression and poor prognosis of tumors. On the other hand, METTL3 may also function as a tumor suppressor in several cancers. Based on the tumor-promoting effect of METTL3, the possibility of applying METTL3 inhibitors is further discussed, which is expected to provide novel insights into antitumor therapy.

Keywords: METTL3; N6-methyladenosine; RNA regulation; Tumorigenesis

DOI: https://doi.org/10.1186/s40364-021-00278-9

Future Oncol. 2021 Apr 21.

Expression profiles and prognostic roles of m6A writers, erasers and readers in gastric cancer.

Jing-Jing Jing, Xu Zhao, Hao Li, Li-Ping Sun, Yuan Yuan.

Aim: To explore the expression profiles of N6-methyladenosine (m6A) enzymes (writers, erasers and readers) and their associations with gastric cancer (GC) prognosis. Methods: Gene expression was analyzed using the UALCAN and Oncomine web resources. The prognostic roles of these genes in GC were analyzed using data from The Cancer Genome Atlas. Results: Thirteen m6A enzymes were found to be upregulated in GC tissues. The expression of m6A writers METTL3, RBM15 and WTAP was associated with pathological stage. The m6A eraser FTO was related to tumor stage and ALKBH5 expression was related to GC prognosis. The m6A reader YTHDF3 expression was associated with tumor stage. YTHDC2 was associated with survival of GC patients. Conclusion: Abnormal changes of key genes involved in m6A RNA methylation may have an important impact on GC development and prognosis.

Keywords: RNA methylation; expression; gastric cancer; m6A

DOI: https://doi.org/10.2217/fon-2020-0630

Int J Biol Sci. 2021 ;17(5): 1178-1190

CircMETTL3, upregulated in a m6A-dependent manner, promotes breast cancer progression.

Zhi Li, Hai-Yan Yang, Xin-Yuan Dai, Xu Zhang, Yu-Zhou Huang, Liang Shi, Ji-Fu Wei, Qiang Ding.

Growing evidence indicates N6-methyladenosine (m6A) has biological function in oncogenesis. METTL3, the catalytic component, is the most important part of methyltransferase complex and plays a crucial role in cancers. However, the biological function of circRNAs derived from METTL3 in breast cancer and the underlying molecular mechanism remains unclear. Herein, we report circMETTL3, which has not been explored in breast cancer, and it is markedly upregulated in breast cancer. Moreover, we uncovered that circMETTL3 could facilitate cell proliferation, migration and invasion in breast cancer. Mechanism investigation showed that circMETTL3 might act as a competing endogenous RNA (ceRNA) of miR-31-5p and upregulate its target cyclin-dependent kinases (CDK1). Moreover, m6A modification of circMETTL3 might affect its expression. Taken together, our results elucidate that circMETTL3 promotes breast cancer progression through circMETTL3/miR-31-5p/CDK1 axis. Moreover, METTL3, the host gene of circMETTL3, may regulate circMETTL3 expression in an m6A-dependent manner, while circMETTL3 has no effect on METTL3 expression, providing a new relationship between the circRNA and the corresponding host gene. Thus, it may serve as a new therapeutic target for breast cancer.

Keywords: CDK1; N6-methyladenosine; breast cancer; circMETTL3; miR-31-5p

DOI: https://doi.org/10.7150/ijbs.57783

Front Cell Dev Biol. 2021 ;9 642443

Dynamics of m6A RNA Methylome on the Hallmarks of Hepatocellular Carcinoma.

Enakshi Sivasudhan, Neil Blake, Zhi-Liang Lu, Jia Meng, Rong Rong.

Epidemiological data consistently rank hepatocellular carcinoma (HCC) as one of the leading causes of cancer-related deaths worldwide, often posing severe economic burden on health care. While the molecular etiopathogenesis associated with genetic and epigenetic modifications has been extensively explored, the biological influence of the emerging field of epitranscriptomics and its associated aberrant RNA modifications on tumorigenesis is a largely unexplored territory with immense potential for discovering new therapeutic approaches. In particular, the underlying cellular mechanisms of different hallmarks of hepatocarcinogenesis that are governed by the complex dynamics of m6A RNA methylation demand further investigation. In this review, we reveal the up-to-date knowledge on the mechanistic and functional link between m6A RNA methylation and pathogenesis of HCC.

Keywords: cancer hallmarks; epitranscriptomics; erasers; hepatocellular carcinoma; m6A RNA methylation; readers; writers

DOI: https://doi.org/10.3389/fcell.2021.642443

J Gene Med. 2021 Apr 24. e3348

Role of FTO gene polymorphisms in Wilms tumor predisposition: a five-center case-control study.

Rui-Xi Hua, Wen Fu, Ao Lin, Haixia Zhou, Jiwen Cheng, Jiao Zhang, Suhong Li, Guochang Liu, Huimin Xia, Zhenjian Zhuo, Jing He.

BACKGROUND: Wilms tumor is the most frequently occurring renal malignancy in pediatrics. The FTO gene exhibits a featured genetic contribution to cancer development. Nonetheless, its single nucleotide polymorphism (SNP) contribution to Wilms tumor is still unknown.
METHODS: Here, 402 Wilms tumor patients and 1198 healthy controls were successfully genotyped for FTO gene SNPs (rs1477196 G>A, rs9939609 T>A, rs7206790 C>G, and rs8047395 A>G) using TaqMan SNP genotyping assays. Odds ratios (ORs) and 95% confidence intervals (CIs), generated from unconditional logistic regression, were applied to quantify the effects of FTO gene SNPs on Wilms tumor risk.
RESULTS: We found that the rs8047395 A>G polymorphism was significantly correlated with an increased risk for Wilms tumor (GG vs. AA/AG: adjusted OR=1.38, 95% CI=1.04-1.85, P=0.027). Carriers with 1 and 1-2 risk genotypes are more susceptible to developing Wilms tumor than those without risk genotypes. Stratified analysis of rs8047395 and risk genotypes revealed more significant relationships to Wilms tumor risk in certain subgroups. Preliminary functional annotations revealed that the rs8047395 A allele increases expression levels of the FTO gene as determined by expression quantitative trait locus (eQTL) analysis.
CONCLUSIONS: Our study provides evidence that rs8047395 may regulate FTO gene expression and thus confer susceptibility to Wilms tumor. The candidate FTO gene rs8047395 A>G polymorphism identified in this study warrants independent investigation.

Keywords: FTO; Wilms tumor; m6A; polymorphism; susceptibility

DOI: https://doi.org/10.1002/jgm.3348

Trends Biochem Sci. 2021 Apr 17. pii: S0968-0004(21)00067-0. [Epub ahead of print]

Histone PTM Crosstalk Stimulates Dot1 Methyltransferase Activity.

Jevon A Cutler, Florian Perner, Scott A Armstrong.

Valencia-Sánchez et al. have demonstrated that two histone post-translational modifications (PTMs) - H4K16 acetylation (H4K16ac) and H2BK120 ubiquitination (H2Bub) - enhance the methylation of H3K79 (H3K79me) by Dot1. This breakthrough indicates crosstalk between H4Kac/H2Bub/H3K79me and may improve our understanding of the role that Dot1/Dot1L plays in developmental processes and disease, including MLL1/KMT2A(MLL-r) leukemia.

Keywords: acetylation; leukemia; methylation; therapeutic targeting; ubiquitination

DOI: https://doi.org/10.1016/j.tibs.2021.04.001