RNA N6‐methyladenosine methyltransferase‐like 3 promotes liver cancer progression through YTHDF2‐dependent posttranscriptional silencing of SOCS2

By Mengnuo Chen, Lai Wei, Cheuk-Ting Law, Felice Ho‐Ching Tsang, Jialing Shen, Carol Cheng, L. Tsang, D. Ho, David Kung‐Chun Chiu, J. Lee and 3 more. Hepatology, 2018

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Epigenetic alterations have contributed greatly to human carcinogenesis. Conventional epigenetic studies have predominantly focused on DNA methylation, histone modifications, and chromatin remodeling. Recently, diverse and reversible chemical modifications of RNAs have emerged as a new layer of epigenetic regulation. N6‐methyladenosine (m6A) is the most abundant chemical modification of eukaryotic messenger RNA (mRNA) and is important for the regulation of mRNA stability, splicing, and translation. Using transcriptome sequencing, we discovered that methyltransferase‐like 3 (METTL3), a major RNA N6‐adenosine methyltransferase, was significantly up‐regulated in human hepatocellular carcinoma (HCC) and multiple solid tumors. Clinically, overexpression of METTL3 is associated with poor prognosis of patients with HCC. Functionally, we proved that knockdown of METTL3 drastically reduced HCC cell proliferation, migration, and colony formation in vitro. Knockout of METTL3 remarkably suppressed HCC tumorigenicity and lung metastasis in vivo. On the other hand, using the CRISPR/dCas9‐VP64 activation system, we demonstrated that overexpression of METTL3 significantly promoted HCC growth both in vitro and in vivo. Through transcriptome sequencing, m6A sequencing, and m6A methylated RNA immuno‐precipitation quantitative reverse‐transcription polymerase chain reaction, we identified suppressor of cytokine signaling 2 (SOCS2) as a target of METTL3‐mediated m6A modification. Knockdown of METTL3 substantially abolished SOCS2 mRNA m6A modification and augmented SOCS2 mRNA expression. We also showed that m6A‐mediated SOCS2 mRNA degradation relied on the m6A reader protein YTHDF2‐dependent pathway. Conclusion: METTL3 is frequently up‐regulated in human HCC and contributes to HCC progression. METTL3 represses SOCS2 expression in HCC through an m6A‐YTHDF2‐dependent mechanism. Our findings suggest an important mechanism of epigenetic alteration in liver carcinogenesis. (Hepatology 2018;67:2254‐2270).

Subfields: Cancer Research, Molecular Biology

View Paper: https://www.semanticscholar.org/paper/9260e0a7ee57537bb10a35979d4fd24b75d455e3

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Citations in the corpus

RNA N6-methyladenosine modification in cancers: current status and perspectives (2018, background): “Similarly, they showed that METTL14 knockdown significantly suppressed HCC cell proliferation, migration and colony formation, and the opposite is true when METTL14 was overexpressed.(87) Thus, they demonstrated that both METTL14 and METTL3 play oncogenic roles in HCC and are required for HCC growth”
Critical Roles of N6-Methyladenosine (m6A) in Cancer and Virus Infection (2020, background): “More importantly, suppressor of cytokine signaling 2 (SOCS2) was identified as a target of METTL3-mediated m6A modification in hepatocellular carcinoma [85].”
The potential role of RNA N6-methyladenosine in Cancer progression (2020, background): “Regarding the molecular mechanism, METTL3 increased the m6A level in SOCS2 mRNA, promoted the degradation of SOCS2 mRNA through an m6AYTHDF2-dependent mechanism, and inhibited the expression of SOCS2 in HCC tissues, thus promoting HCC progression [105].”
m6A mRNA methylation regulates AKT activity to promote the proliferation and tumorigenicity of endometrial cancer (2018, positive): “Although our results suggest that decreased m 6 A methylation promotes tumorigenesis in the endometrium, other cancers are associated with high METTL3 expression and increased m 6 A methylation and could involve different mechanisms 24,32–34 .”
Functions of N6-methyladenosine and its role in cancer (2019, background): “SOCS2 antitumor METTL3↑ YTHDF2 degradation ↓ [113]”
m6A RNA methylation: from mechanisms to therapeutic potential (2021, neutral): “In other cases, such as in hepatocellular carcinoma (HCC), the role of METTL3 and METTL14 is unclear due to contrasting findings regarding whether the m 6 A methyltransferase complex promotes or inhibits cancer pathogenesis (Ma et al , 2017; Chen et al , 2018).”
Histone lactylation drives oncogenesis by facilitating m6A reader protein YTHDF2 expression in ocular melanoma (2021, background): “It was also proven that YTHDF2 causes m(6)A-mediated SOCS2 mRNA degradation and contributes to liver cancer progression [27].”
Methylation multiplicity and its clinical values in cancer (2021, positive): “For instance, the m6A methyl-transferase METTL3 is over-expressed in gastric, colon and liver cancers and promotes cancer cell proliferation via suppressing the tumour suppressor SOCS2 (Refs 109 – 111).”