Abstract
Nasopharyngeal carcinoma (NPC) progression is regulated by genetic, epigenetic, and epitranscript modulation. As one of the epitranscript modifications, the role of N6-Methyladenosine (m6A) has not been elucidated in NPC. In the present study, we found that the poorly methylated gene ZNF750 (encoding zinc finger protein 750) was downregulated in NPC tumor tissues and cell lines. Ectopic expression of ZNF750 blocked NPC growth in vitro and in vivo. Further studies revealed that m6A modifications maintained the low expression level of ZNF750 in NPC. Chromatin immunoprecipitation sequencing identified that ZNF750 directly regulated FGF14 (encoding fibroblast growth factor 14), ablation of which reversed ZNF750’s tumor repressor effect. Moreover, the ZNF750-FGF14 signaling axis inhibited NPC growth by promoting cell apoptosis. These findings uncovered the critical role of m6A in NPC, and stressed the regulatory function of the ZNF750-FGF14 signaling axis in modulating NPC progression, which provides theoretical guidance for the clinical treatment of NPC.
Highlights
Nasopharyngeal carcinoma (NPC) is a malignant head and neck cancer with apparent regional aggregation[1,2,3]
Despite previous findings indicating that Zinc Finger Protein 750 (ZNF750) is frequently mutated in head and neck squamous cell carcinoma (HNSC)[17,18] and esophageal carcinoma (ESCA)[19], ZNF750 was not mutated in the majority of HNSC patients in the cBioPortal dataset[20,21] (Figure S1A, B)
Our work revealed that methyltransferase like 3 (METTL3) mediated m6A modification blocked ZNF750 expression and promoted NPC growth, which presented an example showing m6A played essential regulatory roles posttranscriptionally in NPC
Summary
Nasopharyngeal carcinoma (NPC) is a malignant head and neck cancer with apparent regional aggregation[1,2,3]. With the advancement of intensity-modulated radiation therapy and combined chemotherapy, great progress has been made in local and regional control of NPC. Revealing the underlying mechanism governing NPC progression would identify novel targets to develop clinical treatment strategies. Our previous genome-wide methylation profiling study revealed the methylation status between 24 NPC tissues and 24 normal nasopharyngeal epithelial tissues, from which a list of hypermethylated and hypomethylated genes was composed (GSE52068)[5]. Zinc Finger Protein 750 (ZNF750), as a transcription factor belonging to one of the Zinc Finger Protein family members, was the top-ranked hypomethylated gene in the dataset. The methylated mRNA is recognized by protein “readers” YTH N6-methyladenosine RNA binding protein 1–3
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