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Methyltransferase-like 14 silencing relieves the development of atherosclerosis via m⁶A modification of p65 mRNA.

ABSTRACT: To explore the METTL14-dependent m⁶A modification mechanism involved in the development of atherosclerosis. Oxidized low-density lipoprotein (ox-LDL) and the HUVEC cell line were used to establish an atherosclerosis cell model in vitro, and APOE^-/- mice fed a high-fat diet were used as the animal model. Cell viability and apoptosis were assessed using MTT assays and flow cytometry. The status of m⁶A in HUVECs was examined using MeRIP-qPCR. Oil Red O staining was used to evaluate the lesions or plaques on aortas separated from the target mice. METTL14 and METTL3 were upregulated in HUVECs after ox-LDL treatment. After transfection with si-METTL14, the bcl-2 expression level and the viability of ox-LDL-incubated cells increased, whereas the apoptosis rate and the expressions of Bax and cleaved caspase-3 decreased. However, the effect of METTL14 knockdown was reversed by p65 overexpression. After METTL14 knockdown, there was a decrease in the total m⁶A content in HUVECs, m⁶A modification, and p65 expression. The plaques and lesion areas on the high-fat diet APOE^-/- mouse aortas were smaller after METTL14 silencing. METTL14 reduced cell viability and promoted apoptosis of HUVECs, which were both induced by ox-LDL via m⁶A modification of p65. Knocking down METTL14 could inhibit the development of atherosclerosis in high-fat diet-treated APOE^-/- mice.

SUBMITTER: Liu Y

PROVIDER: S-EPMC9275857 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:BackgroundAs an important N6-methyladenosine (m6A) regulator, abnormal expression of methyltransferase-like protein 3 (METTL3) has been reported in certain human cancers. Although some data have shown that METTL3 plays an essential role in the progression of clear-cell renal cell carcinoma RCC (ccRCC), the detailed mechanism still remains largely undetermined.MethodsImmunohistochemistry (IHC) assay was used to examine the expression of METTL3 and its clinical implications in human ccRCC by using tissue-microarray (TMA). The cellular models based on ccRCC cell lines such as 786-O and ACHN, were established by operating METTL3 and HHLA2 via knockdown or overexpression, followed by in vitro cellular function studies and in vivo subcutaneous transplantation tumor model.ResultsWe found that METTL3 expression in ccRCC tissues was significantly higher compared with adjacent normal tissues. We also found the overall survival (OS) of the patients with low METTL3 expression was significantly better compared with the patients with high METTL3 expression. Furthermore, HHLA2highMETTL3high could serve as a better prognostic predictor for ccRCC patients. Depletion of METTL3 could significantly inhibit the cell viability, migration, and invasion abilities in ccRCC cell lines. Cellular studies further revealed that METTL3 could regulate HHLA2 expression via m6A modification of HHLA2 mRNA. In vitro studies revealed that HHLA2 overexpression could reverse the inhibition of cellular functions mediated by METTL3 depletion. The subcutaneous transplantation tumor model confirmed that HHLA2 overexpression could reverse the inhibition of tumor growth mediated by METTL3 depletion.ConclusionOur study indicated that METTL3 served as an important prognostic predictor for ccRCC patients, and we demonstrated a novel regulatory mechanism of HHLA2 by mRNA epigenetic modification via METTL3. Moreover, we found that the METTL3/HHLA2 axis could promote tumorigenesis of ccRCC. Collectively, our current findings provided new insights into the therapeutic strategy against this malignancy targeting METTL3.

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Methyltransferase-like 14 silencing relieves the development of atherosclerosis via m⁶A modification of p65 mRNA.

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Methyltransferase-like 14 silencing relieves the development of atherosclerosis via m6A modification of p65 mRNA.

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OmicsDI is part of the ELIXIR infrastructure

Tweets

Methyltransferase-like 14 silencing relieves the development of atherosclerosis via m⁶A modification of p65 mRNA.