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METTL3-mediated N6-methyladenosine modification of DUSP5 mRNA promotes gallbladder-cancer progression

Cancer Gene Therapy volume 29, pages 1012–1020 (2022)Cite this article

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Abstract

N6-methyladenosine (m6A) RNA methylation and its associated methyltransferase METTL3 play an important role in tumorigenesis of a series of tumors. However, dysregulation of METTL3 in gallbladder cancer (GBC) remains obscure. Here, we showed that upregulated METTL3 level predicted poor prognosis and correlated with increased lymphatic metastasis and high TNM stage. Functionally, we found that METTL3 could promote cell proliferation, invasion, and migration of GBC-SD and NOZ cells. Mechanistically, we revealed the METTL3-mediated m6A-modification profile in GBC cells and identified DUSP5 as the downstream gene of METTL3. METTL3 promoted the degradation of DUSP5 mRNA in a YTHDF2-dependent manner. Rescue assays showed that downregulation of DUSP5 could attenuate the knockdown METTL3-mediated inhibition of cell proliferation, invasion, and migration of GBC-SD and NOZ cells. Thus, our finding shows that elevated METTL3 expression contributes to tumor aggression in GBC, suggesting that METTL3 is a possible prognostic predictor and therapeutic target against GBC.

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Scheme 1
Fig. 1: METTL3 expression is correlated with poor prognosis in GBC.
Fig. 2: Downregulation of METTL3 expression inhibited GBC cell proliferation, invasion, and migration in vitro.
Fig. 3: METTL3 regulated the expression of several tumor suppressor genes.
Fig. 4: METTL3 downregulated mRNA expression of DUSP5 in a m6A-dependent manner.
Fig. 5: METTL3 promoted the degradation of DUSP5 mRNA in a YTHDF2-dependent manner.
Fig. 6: METTL3 promotes the GBC progression by downregulating DUSP5 expression.

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Authors and Affiliations

  1. Department of Pediatric Surgery, The First Affiliated Hospital of Sun Yat-sen University, Guangzhou, 510080, China

    Hua-Dong Chen, Zhi-Hai Zhong, Peng-Fei Gao & Wen-Zong Gao

  2. State Key Laboratory of Ophthalmology, Zhongshan Ophthalmic Center, Sun Yat-sen University, Guangzhou, 510060, China

    Fuxi Li

  3. Key Laboratory of Stem Cells and Tissue Engineering (Sun Yat-sen University), Ministry of Education, Guangzhou, 510080, China

    Siyun Chen

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  1. Hua-Dong Chen
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Contributions

H.C., F. L., and S. C. performed the experiments and conducted bioinformatics analysis of the sequencing data. S.C. prepared plasmids and lentiviral vectors. Z.Z. and P.G. interpreted the clinical data and revised the paper. H.C. and W.G. designed the experiments, interpreted the data, wrote the paper, and supervised the study.

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Correspondence to Wen-Zong Gao.

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Chen, HD., Li, F., Chen, S. et al. METTL3-mediated N6-methyladenosine modification of DUSP5 mRNA promotes gallbladder-cancer progression. Cancer Gene Ther 29, 1012–1020 (2022). https://doi.org/10.1038/s41417-021-00406-5

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