METTL3/MALAT1/ELAVL1 Axis Promotes Tumor Growth in Ovarian Cancer

Abstract

Background

Studies increasingly recognize the role of N6-methyladenosine (m6A) modification in cancer occurrence and development. METTL3 is a core catalytic subunit of m6A-modified methyltransferases complex, but its regulatory mechanism in ovarian cancer (OC) is not clear.

Methods

In this study, GEPIA 2.0 database was applied for expression analysis, survival analysis and correlation analysis for OC. Additionally, in vitro and in vivo assays were conducted to explore regulatory mechanisms of METTL3 in OC.

Results

We found that METTL3 and MALAT1 were significantly overexpressed in OC tissues and cells compared to normal ovarian tissues and cells. The proliferation rate of OC cells was reduced significantly after knocking down the expression of METTL3 or MALAT1. Subsequently, MALAT1 as oncogene was found to interact with METTL3 and was upregulated in OC tissues and cells. Silencing MALAT1 inhibited OC cell proliferation. Further studies indicated that METTL3 enhanced the stability of MALAT1 by promoting the m6A modification of MALAT1 and that ELAVL1 as a downstream binding protein significantly up-regulated MALAT1 expression.

Conclusion

In conclusion, METTL3 was a carcinogenic molecule that promoted the occurrence of OC. The potential mechanism of the carcinogenic effect of METTL3 was realized by enhancing the m6A modification of MALAT1 mRNA through RNA binding protein ELAVL1.

Keywords:

• N6-methyladenosine
• ovarian cancer
• METTL3
• MALAT1

Data Sharing Statement

The original contributions presented in the study are included in the article/Supplementary File 1. The raw m6A-seq data presented in this study have been deposited in the Genome Sequence Archive in BIG Data Center, Beijing Institute of Genomics (BIG), Chinese Academy of Sciences, under accession number HRA003854 that is accessible at https://bigd.big.ac.cn. Further inquiries can be directed to the first author and corresponding authors.

Ethics Approval and Consent to Participate

The studies involving human ovarian cancer samples were reviewed and approved by the Ethics Committee of Shanghai Outdo Biotech Company (SHYJS-CP-1907005). Our study was also approved by the Ethics Committee of Guangzhou Women and Children’s Medical Center (2022-082B00). The present study was conducted with written informed consent from all of the patients.

Author Contributions

All authors made a significant contribution to the work reported, whether that is in the conception, study design, execution, acquisition of data, analysis and interpretation, or in all these areas; took part in drafting, revising or critically reviewing the article; gave final approval of the version to be published; have agreed on the journal to which the article has been submitted; and agree to be accountable for all aspects of the work.

Disclosure

The authors disclose no conflicts of interest in this work.

Additional information

Funding

This study was funded by the Research foundation of Guangzhou Women and Children’s Medical Center for Clinical Doctor (2021BS044, 2020RC004), and the Science and Technology Program of Guangzhou, China (2024A03J0807, 2024A03J0956).