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METTL3 drives NSCLC metastasis by enhancing CYP19A1 translation and oestrogen synthesis

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Meng, Wangyang, Xiao, Han, Zhao, Rong, Chen, Jiaping, Wang, Yangwei, Mei, Peiyuan, Li, Hecheng, Liao, Yongde·2024·Cell & Bioscience
DOI 10.1186/s13578-024-01194-9PMC PMC10795463

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Abstract

Background: METTL3 plays a significant role as a catalytic enzyme in mediating N6-methyladenosine (m 6 A) modification, and its importance in tumour progression has been extensively studied in recent years. However, the precise involvement of METTL3 in the regulation of translation in non-small cell lung cancer (NSCLC) remains unclear. Results: Here we discovered by clinical investigation that METTL3 expression is correlated with NSCLC metastasis. Ablation of METTL3 in NSCLC cells inhibits invasion and metastasis in vitro and in vivo. Subsequently, through translatomics data mining and experimental validation, we demonstrated that METTL3 enhances the translation of aromatase (CYP19A1), a key enzyme in oestrogen synthesis, thereby promoting oestrogen production and mediating the invasion and metastasis of NSCLC. Mechanistically, METTL3 interacts with translation initiation factors and binds to CYP19A1 mRNA, thus enhancing the translation efficiency of CYP19A1 in an m 6 A-dependent manner. Pharmacological inhibition of METTL3 enzymatic activity or translation initiation factor eIF4E abolishes CYP19A1 protein synthesis. Conclusions: Our findings indicate the crucial role of METTL3-mediated translation regulation in NSCLC and reveal the significance of METTL3/eIF4E/CYP19A1 signaling as a promising therapeutic target for anti-metastatic strategies against NSCLC. Graphical abstract:

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Fig. 1 METTL3 is highly expressed in primary lesions and metastatic lymph nodes of NSCLC, indicating a poor prognosis. (A) The CPTAC database indicates high expression of the METTL3 protein in lung adenocarcinoma tissues. (B) The TCGA database indicates high expression of METTL3 mRNA in NSCLC. (C) Western blot analysis indicates high expression of METTL3 in tumour tissues from 8 NSCLC patients. The right panel displays the quantification results of the left panel. (D) IHC staining of a tissue microarray from 96 patients indicates high expression of METTL3 in primary lesions and metastatic lymph nodes of NSCLC. (E) Quantification results of IHC staining in tissue microarrays. (F) METTL3 expression of primary tumours in N0 stage patients is significantly lower than that in N1-N3 stage patients. (G) DIA-MS results from late-stage NSCLC revealed that METTL3 expression of primary tumours in M0 stage patients is significantly lower than that in M1 stage patients. (H) Survival analysis demonstrates the relationship between METTL3 expression in tissue microarrays and the prognosis of NSCLC patients, with high expression of METTL3 suggesting poor prognosis
Fig. 1 METTL3 is highly expressed in primary lesions and metastatic lymph nodes of NSCLC, indicating a poor prognosis. (A) The CPTAC database indicates high expression of the METTL3 protein in lung adenocarcinoma tissues. (B) The TCGA database indicates high expression of METTL3 mRNA in NSCLC. (C) Western blot analysis indicates high expression of METTL3 in tumour tissues from 8 NSCLC patients. The right panel displays the quantification results of the left panel. (D) IHC staining of a tissue microarray from 96 patients indicates high expression of METTL3 in primary lesions and metastatic lymph nodes of NSCLC. (E) Quantification results of IHC staining in tissue microarrays. (F) METTL3 expression of primary tumours in N0 stage patients is significantly lower than that in N1-N3 stage patients. (G) DIA-MS results from late-stage NSCLC revealed that METTL3 expression of primary tumours in M0 stage patients is significantly lower than that in M1 stage patients. (H) Survival analysis demonstrates the relationship between METTL3 expression in tissue microarrays and the prognosis of NSCLC patients, with high expression of METTL3 suggesting poor prognosisCC BY · PubMed Central
Fig. 2 METTL3 promotes migration, invasion and invadopodia formation in NSCLC cells. (A) Scanning electron microscopy showed that overexpression of METTL3 in A549 and H1975 cells resulted in increased and elongated pseudopodia, while knockout of METTL3 led to decreased and shortened pseudopodia in the cells. (B-C) In the fluorescence matrix degradation experiment, the depth and extent of extracellular matrix degradation were significantly reduced when METTL3 was knocked out in A549 cells using CRISPR‒Cas9 technology. Furthermore, the depth and extent of extracellular matrix degradation were reduced in H1975 cells after METTL3 knockdown. (D-E) The wound healing experiment after METTL3 knockout demonstrated a significant decrease in cell migration ability in A549 cells. After transfection with siRNA targeting METTL3, there is a significant decrease in the migration ability of H1975 cells. (F-G) Transwell invasion experiments after METTL3 knockout showed a significant decrease in cell invasion ability of A549 cells. After transfection with siRNA targeting METTL3, there is a significant decrease in the invasion ability of H1975 cells
Fig. 2 METTL3 promotes migration, invasion and invadopodia formation in NSCLC cells. (A) Scanning electron microscopy showed that overexpression of METTL3 in A549 and H1975 cells resulted in increased and elongated pseudopodia, while knockout of METTL3 led to decreased and shortened pseudopodia in the cells. (B-C) In the fluorescence matrix degradation experiment, the depth and extent of extracellular matrix degradation were significantly reduced when METTL3 was knocked out in A549 cells using CRISPR‒Cas9 technology. Furthermore, the depth and extent of extracellular matrix degradation were reduced in H1975 cells after METTL3 knockdown. (D-E) The wound healing experiment after METTL3 knockout demonstrated a significant decrease in cell migration ability in A549 cells. After transfection with siRNA targeting METTL3, there is a significant decrease in the migration ability of H1975 cells. (F-G) Transwell invasion experiments after METTL3 knockout showed a significant decrease in cell invasion ability of A549 cells. After transfection with siRNA targeting METTL3, there is a significant decrease in the invasion ability of H1975 cellsCC BY · PubMed Central
Fig. 3 METTL3 depletion inhibits metastatic potential of lung cancer cells in vivo. (A) Macroscopic image of mouse lungs injected with NC-METTL3 cells and KO-METTL3 cells via the tail vein. The NC-METTL3 group exhibited a significantly higher number of metastatic tumours than the KO-METTL3 group. (B) Histological sections of mouse lungs with HE staining. The NC-METTL3 group showed a significantly higher number of metastatic noduless than the KO-METTL3 group. (C) Quantification of lung metastatic nodules in mice from the NC-METTL3 group and the KO-METTL3 group. The NC-METTL3 group demonstrated significantly more lung metastatic tumours than the KO-METTL3 group. (D) Kaplan‒Meier survival curves for the KO-NC group and KO-METTL3 group
Fig. 3 METTL3 depletion inhibits metastatic potential of lung cancer cells in vivo. (A) Macroscopic image of mouse lungs injected with NC-METTL3 cells and KO-METTL3 cells via the tail vein. The NC-METTL3 group exhibited a significantly higher number of metastatic tumours than the KO-METTL3 group. (B) Histological sections of mouse lungs with HE staining. The NC-METTL3 group showed a significantly higher number of metastatic noduless than the KO-METTL3 group. (C) Quantification of lung metastatic nodules in mice from the NC-METTL3 group and the KO-METTL3 group. The NC-METTL3 group demonstrated significantly more lung metastatic tumours than the KO-METTL3 group. (D) Kaplan‒Meier survival curves for the KO-NC group and KO-METTL3 groupCC BY · PubMed Central
Fig. 4 CYP19A1 is the potential target of METTL3-mediated translation regulation. (A-B) GO-KEGG analysis and GSEA of genes with decreased translation efficiency after METTL3 knockout indicated the association between METTL3 and the steroid signalling pathway. (C) Genes downregulated in translation efficiency after METTL3 depletion were crossed with genes involved in steroid biosynthetic processes and the cytochrome P450 enzyme system to obtain CYP19A1. (D-E) IHC staining analysis of patient tissue microarray showed that compared to adjacent tissues, CYP19A1 protein was highly expressed in both the primary lesions and metastatic lymph nodes of NSCLC. (F) The results of IHC analysis indicated that CYP19A1 expression was positively correlated with METTL3 expression in NSCLC. (G) Survival analysis of the tissue microarray indicated that high expression of CYP19A1 suggests poor prognosis of NSCLC patients. (H) Western blotting analysis validated that the CYP19A1 protein is highly expressed in NSCLC tissues compared with paired normal lung tissues. (I) Data from the TCGA database indicated that CYP19A1 mRNA expression in NSCLC is lower than that in normal lung tissue. (J) RT‒qPCR indicated that CYP19A1 mRNA expression in NSCLC is not higher than that in paired normal lung tissue
Fig. 4 CYP19A1 is the potential target of METTL3-mediated translation regulation. (A-B) GO-KEGG analysis and GSEA of genes with decreased translation efficiency after METTL3 knockout indicated the association between METTL3 and the steroid signalling pathway. (C) Genes downregulated in translation efficiency after METTL3 depletion were crossed with genes involved in steroid biosynthetic processes and the cytochrome P450 enzyme system to obtain CYP19A1. (D-E) IHC staining analysis of patient tissue microarray showed that compared to adjacent tissues, CYP19A1 protein was highly expressed in both the primary lesions and metastatic lymph nodes of NSCLC. (F) The results of IHC analysis indicated that CYP19A1 expression was positively correlated with METTL3 expression in NSCLC. (G) Survival analysis of the tissue microarray indicated that high expression of CYP19A1 suggests poor prognosis of NSCLC patients. (H) Western blotting analysis validated that the CYP19A1 protein is highly expressed in NSCLC tissues compared with paired normal lung tissues. (I) Data from the TCGA database indicated that CYP19A1 mRNA expression in NSCLC is lower than that in normal lung tissue. (J) RT‒qPCR indicated that CYP19A1 mRNA expression in NSCLC is not higher than that in paired normal lung tissueCC BY · PubMed Central
Fig. 5 METTL3 mediates m6A modification of CYP19A1 and promotes the synthesis of E2. (A) WB experiments demonstrated that knockdown of METTL3 using siRNA significantly reduced the protein expression of CYP19A1. (B) PCR experiments showed an upwards trend in the mRNA expression of CYP19A1 following siRNA knockdown of METTL3. (C) ELISA revealed a decrease in intracellular and extracellular levels of E2 after siRNA knockdown of METTL3. (D) CYP19A1 is upregulated after transfection of plasmids for METTL3 overexpression. (E) Protein expression of CYP19A1 is significantly downregulated after CRISPR‒Cas9 knockout of METTL3. (F) PCR indicated an upwards trend in the mRNA expression of CYP19A1 following CRISPR‒Cas9 knockout of METTL3. (G) ELISA demonstrated a significant decrease in intracellular and extracellular levels of E2 after CRISPR‒Cas9 knockout of METTL3. (H) Treatment with 5 µM STM2457 for 3 days led to a significant decrease in the protein level of CYP19A1. (I) Treatment with 5 µM STM2457 for 3 days led to a significant increase in the mRNA level of CYP19A1. (J) Treatment with 5 µM STM2457 for 3 days led to a significant reduction in E2 levels. (K) MeRIP-qPCR revealed that CYP19A1 mRNA was enriched in m6A modification and the relative levels of m6A whin CYP19A1 were significantly downregulated after METTL3 knockout in A549 cells. (L) MeRIP-qPCR revealed that CYP19A1 mRNA was enriched in m6A modification in H1975 cells. (M-N) CYP19A1 protein expression and intratumoural E2 concentration in lung metastasis of KO-METTL3 tumours are significantly downregulated
Fig. 5 METTL3 mediates m6A modification of CYP19A1 and promotes the synthesis of E2. (A) WB experiments demonstrated that knockdown of METTL3 using siRNA significantly reduced the protein expression of CYP19A1. (B) PCR experiments showed an upwards trend in the mRNA expression of CYP19A1 following siRNA knockdown of METTL3. (C) ELISA revealed a decrease in intracellular and extracellular levels of E2 after siRNA knockdown of METTL3. (D) CYP19A1 is upregulated after transfection of plasmids for METTL3 overexpression. (E) Protein expression of CYP19A1 is significantly downregulated after CRISPR‒Cas9 knockout of METTL3. (F) PCR indicated an upwards trend in the mRNA expression of CYP19A1 following CRISPR‒Cas9 knockout of METTL3. (G) ELISA demonstrated a significant decrease in intracellular and extracellular levels of E2 after CRISPR‒Cas9 knockout of METTL3. (H) Treatment with 5 µM STM2457 for 3 days led to a significant decrease in the protein level of CYP19A1. (I) Treatment with 5 µM STM2457 for 3 days led to a significant increase in the mRNA level of CYP19A1. (J) Treatment with 5 µM STM2457 for 3 days led to a significant reduction in E2 levels. (K) MeRIP-qPCR revealed that CYP19A1 mRNA was enriched in m6A modification and the relative levels of m6A whin CYP19A1 were significantly downregulated after METTL3 knockout in A549 cells. (L) MeRIP-qPCR revealed that CYP19A1 mRNA was enriched in m6A modification in H1975 cells. (M-N) CYP19A1 protein expression and intratumoural E2 concentration in lung metastasis of KO-METTL3 tumours are significantly downregulatedCC BY · PubMed Central
Fig. 6 Translation of CYP19A1 mRNA is dependent on the regulation of METTL3. (A) In KO-METTL3 cells, the transient transfection of plasmids was used to upregulate the mRNA levels of CYP19A1, while METTL3 deficiency abolished its effect on CYP19A1 protein expression. However, in the KO-NC group, transient overexpression of CYP19A1 mRNA successfully led to overexpressed CYP19A1 protein. (B) PCR results showed that both the KO-METTL3 and KO-NC groups transfected with plasmids transiently overexpressed CYP19A1 mRNA. (C) In the KO-NC group, transient overexpression of CYP19A1 mRNA led to upregulation of E2 levels, while in the KO-METTL3 group, METTL3 deficiency decreased intracellular and extracellular E2 secretion. (D) Wound healing experiments showed that in the KO-NC group, transient upregulation of CYP19A1 mRNA significantly enhanced cell migration ability. However, transient upregulation of CYP19A1 mRNA did not significantly alter the cell migration ability under METTL3 deficiency. (E) Transwell invasion assay showed that in the KO-NC group, transient upregulation of CYP19A1 mRNA significantly enhanced cell invasion ability. However, transient upregulation of CYP19A1 mRNA did not significantly alter the cell invasion ability under METTL3 deficiency
Fig. 6 Translation of CYP19A1 mRNA is dependent on the regulation of METTL3. (A) In KO-METTL3 cells, the transient transfection of plasmids was used to upregulate the mRNA levels of CYP19A1, while METTL3 deficiency abolished its effect on CYP19A1 protein expression. However, in the KO-NC group, transient overexpression of CYP19A1 mRNA successfully led to overexpressed CYP19A1 protein. (B) PCR results showed that both the KO-METTL3 and KO-NC groups transfected with plasmids transiently overexpressed CYP19A1 mRNA. (C) In the KO-NC group, transient overexpression of CYP19A1 mRNA led to upregulation of E2 levels, while in the KO-METTL3 group, METTL3 deficiency decreased intracellular and extracellular E2 secretion. (D) Wound healing experiments showed that in the KO-NC group, transient upregulation of CYP19A1 mRNA significantly enhanced cell migration ability. However, transient upregulation of CYP19A1 mRNA did not significantly alter the cell migration ability under METTL3 deficiency. (E) Transwell invasion assay showed that in the KO-NC group, transient upregulation of CYP19A1 mRNA significantly enhanced cell invasion ability. However, transient upregulation of CYP19A1 mRNA did not significantly alter the cell invasion ability under METTL3 deficiencyCC BY · PubMed Central
Fig. 7 METTL3 binds to CYP19A1 mRNA and interact with eIFs to regulates translation efficiency of CYP19A1. (A) Immunoprecipitation using anti-METTL3 followed by mass spectrometry analysis was performed to identify proteins that interact with METTL3. A total of 218 proteins were identified as specific binding proteins of METTL3, which are presented in a Venn diagram. GO analysis of the 218 proteins revealed enrichment in the translation initiation process. (B) Co-IP to confirm the interaction between METTL3 and translation initiation molecules identified by mass spectrometry, including eIF3e, eIF3i, and eIF4E. (C-D) RNA immunoprecipitation using anti-METTL3 antibody followed by qPCR validation showing direct binding of METTL3 to CYP19A1 mRNA in A549 and H1975 cells. Agarose gel electrophoresis of qPCR samples confirmed the enrichment of CYP19A1 mRNA in the anti-METTL3 group, confirming the binding between METTL3 and CYP19A1 mRNA. (E) Treatment with the eIF4E inhibitor 4EGI-1 significantly downregulated the protein expression of CYP19A1. (F) Administration of 4EGI-1 abolished the effect of METTL3 overexpression in promoting CYP19A1 expression
Fig. 7 METTL3 binds to CYP19A1 mRNA and interact with eIFs to regulates translation efficiency of CYP19A1. (A) Immunoprecipitation using anti-METTL3 followed by mass spectrometry analysis was performed to identify proteins that interact with METTL3. A total of 218 proteins were identified as specific binding proteins of METTL3, which are presented in a Venn diagram. GO analysis of the 218 proteins revealed enrichment in the translation initiation process. (B) Co-IP to confirm the interaction between METTL3 and translation initiation molecules identified by mass spectrometry, including eIF3e, eIF3i, and eIF4E. (C-D) RNA immunoprecipitation using anti-METTL3 antibody followed by qPCR validation showing direct binding of METTL3 to CYP19A1 mRNA in A549 and H1975 cells. Agarose gel electrophoresis of qPCR samples confirmed the enrichment of CYP19A1 mRNA in the anti-METTL3 group, confirming the binding between METTL3 and CYP19A1 mRNA. (E) Treatment with the eIF4E inhibitor 4EGI-1 significantly downregulated the protein expression of CYP19A1. (F) Administration of 4EGI-1 abolished the effect of METTL3 overexpression in promoting CYP19A1 expressionCC BY · PubMed Central

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Metadata

Authors
Meng, W., Xiao, H., Zhao, R., Chen, J., Wang, Y., Mei, P., Li, H., & Liao, Y.
Affiliations
  • Shanghai Jiao Tong University (CN)
  • Huazhong University of Science and Technology (CN)
  • Kunming Medical University (CN)
  • Wuhan Union Hospital (CN)
Corresponding author
  • Li, Hecheng
  • Liao, Yongde
ORCID
Venue
Cell & Bioscience
Publisher
Springer Science and Business Media LLC
Published
2024-01-18
Volume
14
Issue
1
Pages
10-10
ISSN
2045-3701 (ISSN-L)
DOI
10.1186/s13578-024-01194-9
PMC
PMC10795463
OpenAlex
W4391011947
Cited by
16
References
1
Citations by year
2026: 4 · 2025: 8 · 2024: 4
FWCI
2.17
Type
journal article
Language
en
Open access
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Locations
  • Cell & Bioscience (publishedVersion, cc-by)
  • Research Square (acceptedVersion, cc-by)
  • PubMed Central (publishedVersion, cc-by)
  • PubMed (publishedVersion)
  • DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
Funders
  • National Natural Science Foundation of China (82072593)
  • Department of Science and Technology, Hubei Provincial People’s Government (2020BCB027)
Topics
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › RNA modifications and cancer
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › RNA and protein synthesis mechanisms
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › PI3K/AKT/mTOR signaling in cancer
Keywords
METTL3, non-small cell lung cancer, metastasis, CYP19A1, aromatase, estrogen synthesis, N6-methyladenosine, mRNA methylation, translational regulation, eIF4E, translation initiation factors, tumor invasion, therapeutic target

About these checks

Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.

Statistics and arithmetic are recomputed, not judged.

Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.

What counts as a claim ›How we measure confidence ›How we check this ›

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How to cite

Cite CoChat for the checks on this page, and the paper for its own findings.

This page
CoChat. (2026). Citation check: METTL3 drives NSCLC metastasis by enhancing CYP19A1 translation and oestrogen synthesis. https://app.cochat.ai/papers/10.1186/s13578-024-01194-9
The paper
Meng, W., Xiao, H., Zhao, R., Chen, J., Wang, Y., Mei, P., Li, H., & Liao, Y. (2024). METTL3 drives NSCLC metastasis by enhancing CYP19A1 translation and oestrogen synthesis. Cell & Bioscience. https://doi.org/10.1186/s13578-024-01194-9