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Analysis of METTL3 and METTL14 in hepatocellular carcinoma
Xiangxiang Liu1, Jian Qin2, Tianyi Gao2
1School of Medicine, Southeast University, Nanjing 210096, Jiangsu, China.
Abstract:
N6-methyladenosine (m6A) RNA methylation is the most prevalent modification of messenger RNAs (mRNAs) and catalyzed by a multicomponent methyltransferase complex (MTC), among which methyltransferase-like 3 (METTL3) and METTL14 are two core molecules. However, METTL3 and METTL14 play opposite regulatory roles in hepatocellular carcinoma (HCC). Based on The Cancer Genome Atlas (TCGA) database and Gene Expression Omnibus (GEO) database, we conducted a multi-omics analysis of METTL3 and METTL14 in HCC, including RNA-sequencing, m6ARIP-sequencing, and ribosome-sequencing profiles. We found that the expression and prognostic value of METTL3 and METTL14 are opposite in HCC. Besides, after METTL3 and METTL14 knockdown, most of the dysregulated mRNAs, signaling pathways and biological processes are distinct in HCC, which partly explains the contrary regulatory role of METTL3 and METTL14. Intriguingly, these mRNAs whose stability or translation efficiency are influenced by METTL3 or METTL14 in an m6A dependent manner, jointly regulate multiple signaling pathways and biological processes, which supports the cooperative role of METTL3 and METTL14 in catalyzing m6A modification. In conclusion, our study further clarified the contradictory role of METTL3 and METTL14 in HCC.
Insights
Methyltransferase-like 3 (METTL3) and METTL14 have opposing roles in liver cancer (HCC). This study clarifies their distinct yet cooperative functions in m6A RNA methylation, impacting mRNA stability and translation.
Area of Science:
- Molecular Biology
- Epigenetics
- Oncology
Background:
- N6-methyladenosine (m6A) is the most abundant RNA modification.
- METTL3 and METTL14 are key components of the m6A methyltransferase complex (MTC).
- METTL3 and METTL14 exhibit opposing regulatory roles in hepatocellular carcinoma (HCC).
Purpose of the Study:
- To investigate the distinct and cooperative roles of METTL3 and METTL14 in HCC.
- To analyze the multi-omics data of METTL3 and METTL14 in HCC.
- To elucidate the mechanisms underlying their contradictory functions.
Main Methods:
- Multi-omics analysis using TCGA and GEO databases.
- RNA-sequencing, m6ARIP-sequencing, and ribosome-sequencing.
- Knockdown experiments to assess gene and pathway dysregulation.
Main Results:
- METTL3 and METTL14 show inverse expression patterns and prognostic values in HCC.
- Knockdown of METTL3 or METTL14 leads to distinct sets of dysregulated mRNAs, pathways, and biological processes.
- m6A-dependent regulation of mRNA stability and translation by METTL3 and METTL14 impacts shared pathways.
Conclusions:
- METTL3 and METTL14 play contradictory roles in HCC progression.
- Their distinct regulatory effects on mRNA targets contribute to their opposing functions.
- METTL3 and METTL14 cooperate in m6A modification, influencing HCC-related signaling and processes.
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