Abstract
As the most predominant RNA epigenetic regulation in eukaryotic cells, N6-methyladenosine (m6A) plays a critical role in human tumorigenesis and cancer progression. However, the biological function and molecular mechanism of m6A regulation in naso-pharyngeal carcinoma (NPC) remain elusive. Here, we showed that Wilms’ tumor 1-associating protein (WTAP) expression was apparently upregulated in NPC, and increased WTAP was associated with poor prognosis. WTAP upregulated in NPC was fine-tuned by KAT3A-mediated H3K27 acetylation. Functionally, WTAP was required for the growth and metastasis of NPC. Mechanistically, lncRNA DIAPH1-AS1 was identified as a bona fide m6A target of WTAP. WTAP-mediated m6A modification of DIAPH1-AS1 enhanced its stability relying on the m6A reader IGF2BP2-dependent pathway. Furthermore, DIAPH1-AS1 acted as a molecular adaptor that promoted MTDH-LASP1 complex formation and upregulated LASP1 expression, ultimately facilitating NPC growth and metastasis. Thus, WTAP-mediated DIAPH1-AS1 m6A methylation is required for NPC tumorigenesis and metastasis.
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Data availability
The source data that support the findings of this study are available to readers. MeRIP profiles are accessible at the GEO repository under accession number GSE160644.
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Acknowledgements
We thank Dr. M. Zeng from Sun Yat-Sen University Cancer Center for providing NPC and immortalized nasopharyngeal epithelial cell lines.
Funding
This work was supported by grants from the National Natural Science Foundation of China (No. 81902762, No. 82002220), the Health & Medical Collaborative Innovation Project of Guangzhou City, China (No. 201604020003, 201803040003), the Special Support Program of Sun Yat-sen University Cancer Center (16zxtzlc06), the Natural Science Foundation of Guangdong Province (No. 2019A1515012045), the Innovation Team Development Plan of the Ministry of Education (No. IRT_17R110), and the National Key R&D Program of China (2016YFC0902000). The datasets generated and/or analyzed during the current study are available at the Research Data Deposit public platform (www.researchdata.org.cn).
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Conceptualization, Z.X.L., Y.S.; Data production, analysis and investigation, Z.X.L., Z.Q.Z., P.Y.Y., L.L., G.Q.Z., J.W.L., L.L.Z., F.P.C., Y.Q.L., C.F.W., F.L., and J.M.; Writing, Review and Edit, Z.Q.Z, Z.X.L., and Y.S.; Supervision, N.L., Y.S.; Funding acquisition, L.L. and Y.S. The author(s) read and approved the final manuscript.
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This study was approved by the Institutional Review Board of Sun Yat-Sen University Cancer Center (GZR2020-220). All animal experiments conducted was compliant with Institutional Animal Care and Use Committee, Sun Yat-sen University Cancer Center (L102012019110C).
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Li, ZX., Zheng, ZQ., Yang, PY. et al. WTAP-mediated m6A modification of lncRNA DIAPH1-AS1 enhances its stability to facilitate nasopharyngeal carcinoma growth and metastasis. Cell Death Differ 29, 1137–1151 (2022). https://doi.org/10.1038/s41418-021-00905-w
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DOI: https://doi.org/10.1038/s41418-021-00905-w
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