Dataset Information

METTL3-mediated m⁶A mRNA modification of FBXW7 suppresses lung adenocarcinoma.

ABSTRACT:

Background

FBXW7 m⁶A modification plays an important role in lung adenocarcinoma (LUAD) progression; however, the underlying mechanisms remain unclear.

Methods

The correlation between FBXW7 and various genes related to m⁶A modification was analyzed using The Cancer Genome Atlas database. The regulatory effects of METTL3 on FBXW7 mRNA m⁶A modification were examined in a cell model, and the underlying mechanism was determined by methylated RNA immunoprecipitation, RNA immunoprecipitation, luciferase reporter, and mutagenesis assays. In vitro experiments were performed to further explore the biological effects of METTL3-mediated FBXW7 m⁶A modification on LUAD development.

Results

Decreased FBXW7 expression was accompanied by downregulated METTL3 expression in human LUAD tissues and was associated with a worse prognosis for LUAD in The Cancer Genome Atlas database. m⁶A was highly enriched in METTL3-mediated FBXW7 transcripts, and increased m⁶A modification in the coding sequence region increased its translation. Functionally, METTL3 overexpression or knockdown affected the apoptosis and proliferation phenotype of LUAD cells by regulating FBXW7 m⁶A modification and expression. Furthermore, FBXW7 overexpression in METTL3-depleted cells partially restored LUAD cell suppression in vitro and in vivo.

Conclusions

Our findings reveal that METTL3 positively regulates FBXW7 expression and confirm the tumor-suppressive role of m⁶A-modified FBXW7, thus providing insight into its epigenetic regulatory mechanisms in LUAD initiation and development.

SUBMITTER: Wu Y

PROVIDER: S-EPMC7936500 | biostudies-literature | 2021 Mar

REPOSITORIES: biostudies-literature

ACCESS DATA

Publications

METTL3-mediated m<sup>6</sup>A mRNA modification of FBXW7 suppresses lung adenocarcinoma.

Wu Yingtong Y Chang Ning N Zhang Yong Y Zhang Xinxin X Xu Leidi L Che Yinggang Y Qiao Tianyun T Wu Bin B Zhou Ying Y Jiang Jun J Xiong Jie J Zhang Jian J Zhang Jian J

Journal of experimental & clinical cancer research : CR 20210306 1

<h4>Background</h4>FBXW7 m<sup>6</sup>A modification plays an important role in lung adenocarcinoma (LUAD) progression; however, the underlying mechanisms remain unclear.<h4>Methods</h4>The correlation between FBXW7 and various genes related to m<sup>6</sup>A modification was analyzed using The Cancer Genome Atlas database. The regulatory effects of METTL3 on FBXW7 mRNA m<sup>6</sup>A modification were examined in a cell model, and the underlying mechanism was determined by methylated RNA immuno ...[more]

PMID: 33676554

Similar Datasets

Project description:BackgroundN6-methyladenosine (m6A) has emerged as a significant regulator of the progress of various cancers. However, its role in lung adenocarcinoma (LUAD) remains unclear. Here, we explored the biological function and underlying mechanism of methyltransferase-like 3 (METTL3), the main catalyst of m6A, in LUAD progression.MethodsThe expression of m6A, METTL3, YTHDF1 and SLC7A11 were detected by immunochemistry or/and online datasets in LUAD patients. The effects of METTL3 on LUAD cell proliferation, apoptosis and ferroptosis were assessed through in vitro loss-and gain-of-function experiments. The in vivo effect on tumorigenesis of METTL3 was evaluated using the LUAD cell xenograft mouse model. MeRIP-seq, RNA immunoprecipitation and RNA stability assay were conducted to explore the molecular mechanism of METTL3 in LUAD.ResultsThe results showed that the m6A level, as well as the methylase METTL3 were both significantly elevated in LUAD patients and lung cancer cells. Functionally, we found that METTL3 could promote proliferation and inhibit ferroptosis in different LUAD cell models, while METTL3 knockdown suppressed LUAD growth in cell-derived xenografts. Mechanistically, solute carrier 7A11 (SLC7A11), the subunit of system Xc-, was identified as the direct target of METTL3 by mRNA-seq and MeRIP-seq. METTL3-mediated m6A modification could stabilize SLC7A11 mRNA and promote its translation, thus promoting LUAD cell proliferation and inhibiting cell ferroptosis, a novel form of programmed cell death. Additionally, we demonstrated that YTHDF1, a m6A reader, was recruited by METTL3 to enhance SLC7A11 m6A modification. Moreover, the expression of YTHDF1 and SLC7A11 were positively correlated with METTL3 and m6A in LUAD tissues.ConclusionsThese findings reinforced the oncogenic role of METTL3 in LUAD progression and revealed its underlying correlation with cancer cell ferroptosis; these findings also indicate that METTL3 is a promising novel target in LUAD diagnosis and therapy.

Dataset Information

METTL3-mediated m⁶A mRNA modification of FBXW7 suppresses lung adenocarcinoma.

Background

Methods

Results

Conclusions

Publications

METTL3-mediated m<sup>6</sup>A mRNA modification of FBXW7 suppresses lung adenocarcinoma.

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets

Dataset Information

METTL3-mediated m6A mRNA modification of FBXW7 suppresses lung adenocarcinoma.

Background

Methods

Results

Conclusions

Publications

METTL3-mediated m<sup>6</sup>A mRNA modification of FBXW7 suppresses lung adenocarcinoma.

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets

METTL3-mediated m⁶A mRNA modification of FBXW7 suppresses lung adenocarcinoma.