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An alternatively spliced variant of METTL3 mediates tumor suppression in hepatocellular carcinoma

ABSTRACT: Many steps of post-transcriptional mRNA processing have shown crucial roles in the tumorigenesis and progression of cancers, such as the N6-methyladenosine (m6A) modification and alternative splicing. Up-regulation of METTL3, the catalytic core of the m6A methyltransferase complex, increases the m6A levels and results in significant effects on the progression of hepatocellular carcinoma (HCC). However, alternative splicing of METTL3 has not been fully investigated and functions of its splice variants remain unclear. Here, we first analyze online and our transcriptomic data and obtain 13 splice variants of METTL3 besides the canonical full-length METTL3-A in HCC cell lines and tissues. Validated by RT-qPCR, we find that METTL3-D, one of the splice variants expressing a truncated METTL3 protein, exhibits higher levels than the METTL3-A in normal human livers but lower levels in HCC tumor tissues and cell lines. Further functional assays demonstrate that expression of METTL3-D decreases the cellular m6A modification, inhibits the proliferation, migration and invasion of HCC cells, and is negatively associated with the malignancy of patient tumors, exhibiting an opposite function as the full-length METTL3-A does. Analyses of TCGA data also show that HCC patients with higher levels of METTL3-D have longer survivals. This study demonstrates that the METTL3-D splice variant is a tumor suppressor, and it could be used as a potential target for the therapy of HCC.

ORGANISM(S): Homo sapiens

PROVIDER: GSE189372 | GEO | 2022/05/01

REPOSITORIES: GEO

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