SUMO1 modification of methyltransferase-like 3 promotes tumor progression via regulating Snail mRNA homeostasis in hepatocellular carcinoma.

Rationale: Hepatocellular carcinoma (HCC) is one of the leading causes of mortality worldwide. Methyltransferase-like 3 (Mettl3), an RNA N6-methyladenosine (m6A) methyltransferase, has been shown to act as an oncogene in several human cancers. However, the regulatory role of posttranslational modifications of Mettl3 in liver cancer remains elusive. Methods: SUMOylation was analyzed using immunoprecipitation and western blot assays. In vitro and in vivo biological functions were examined using MTS, colony formation, wound healing, transwell, apoptosis, and viability assays and the BALB/c nude mouse model, respectively. Immunohistochemistry was conducted to evaluate the prognostic value of Mettl3 expression in HCC. The regulatory mechanism of Mettl3 in HCC was investigated by m6A dot blot, immunofluorescence, dual luciferase reporter, protein stability, and RNA stability assays. Results: Mettl3 was found to be SUMOylated by a small ubiquitin-like modifier SUMO1. Further, SUMOylation of Mettl3 was increased upon mitogen stimulation, which correlated with UBC9 upregulation, and was positively correlated with high metastatic potential of liver cancer. Finally, SUMOylation of Mettl3 was found to regulate HCC progression via controlling Snail mRNA homeostasis in an m6A methyltransferase activity-dependent manner. Conclusions: This study revealed a novel mechanism of SUMOylated Mettl3-mediated Snail mRNA homeostasis, identifying the UBC9/SUMOylated Mettl3/Snail axis as a novel mediator of the SUMO pathway involved in HCC progression.

Xu H ，Wang H ，Zhao W ，Fu S ，Li Y ，Ni W ，Xin Y ，Li W ，Yang C ，Bai Y ，Zhan M ，Lu L ... -  《Theranostics》

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

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. 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).

Chen M ，Wei L ，Law CT ，Tsang FH ，Shen J ，Cheng CL ，Tsang LH ，Ho DW ，Chiu DK ，Lee JM ，Wong CC ，Ng IO ，Wong CM ... -  《-》

WTAP facilitates progression of hepatocellular carcinoma via m6A-HuR-dependent epigenetic silencing of ETS1.

Chen Y ，Peng C ，Chen J ，Chen D ，Yang B ，He B ，Hu W ，Zhang Y ，Liu H ，Dai L ，Xie H ，Zhou L ，Wu J ，Zheng S ... -  《Molecular Cancer》

SUMOylation of the m6A-RNA methyltransferase METTL3 modulates its function.

Du Y ，Hou G ，Zhang H ，Dou J ，He J ，Guo Y ，Li L ，Chen R ，Wang Y ，Deng R ，Huang J ，Jiang B ，Xu M ，Cheng J ，Chen GQ ，Zhao X ，Yu J ... -  《-》

RNA m6A methylation promotes the formation of vasculogenic mimicry in hepatocellular carcinoma via Hippo pathway.

Qiao K ，Liu Y ，Xu Z ，Zhang H ，Zhang H ，Zhang C ，Chang Z ，Lu X ，Li Z ，Luo C ，Liu Y ，Yang C ，Sun T ... -  《-》