MFSD4A inhibits the malignant progression of nasopharyngeal carcinoma by targeting EPHA2

Abstract

DNA Methylation can lead to abnormal gene expression. In the present study, we investigated whether the expression of methylated MFSD4A (major facilitator superfamily domain containing 4 A) was downregulated in nasopharyngeal carcinoma (NPC) and whether it is associated with malignant progression and poor prognosis of NPC. Bioinformatic analysis, bisulfite pyrosequencing, quantitative real-time reverse transcription PCR, and western blotting assays were performed to explore the relationship between hypermethylation of MFSD4A and its expression in NPC. The role of MFSD4A in NPC was verified by Cell Cycle Kit 8, transwell assays and flow cytometry in vitro and by animal experiments in vivo. Mass spectrometry, co-immunoprecipitation, and immunofluorescence assays were applied to explore the mechanism by which MFSD4A inhibits NPC. The prognostic significance of MFSD4A or EPHA2 was investigated by immunohistochemical analysis of clinical specimens. Hypermethylation of the promoter region of MFSD4A led to decreased expression of MFSD4A. When MFSD4A expression was upregulated or downregulated, the proliferation, apoptosis, migration, and invasion abilities of NPC cells were altered accordingly. Mechanistically, MFSD4A could specifically bind to and degrade EPH receptor A2 (EPHA2) by recruiting ring finger protein 149 (RNF149), which led to alterations in the EPHA2-mediated PI3K-AKT-ERK1/2 pathway and epithelial-mesenchymal transition (EMT), thereby affecting NPC progression. Clinically, high MFSD4A expression or low-EPHA2 expression was associated with better prognosis for patients with NPC. In all, reduced MFSD4A expression in NPC is caused by promoter hypermethylation. MFSD4A or EPHA2 expression is associated with the malignant biological behavior and prognosis of NPC. MFSD4A is a promising potential therapeutic target for NPC.

RNF149 Promotes HCC Progression through Its E3 Ubiquitin Ligase Activity

“…However, reports regarding its functions in cells are few. It has been reported that RNF149 promotes cell survival in colorectal cancer [10] and inhibits cell migration in NPC [11]. Additionally, RNF149 is found to involve the development of rat neonatal gonocytes [29].…”

“…As an E3 ubiquitin ligase, only two experimentally validated substrates of RNF149 were reported so far: wild-type but not mutant BRAF in colorectal cancer [10], and EPHA2 in NPC [11]. To discover the substrate of RNF149 in HCC, we focused on the proteins which both showed significant downregulation in RNF149-overexpressed HCC cells and interacted with RNF149, and DNAJC25 was the only candidate with high confidence.…”

“…In colorectal cancer, RNF149 selectively degrades wild-type B-RAF instead of mutant B-RAF [10]. In nasopharyngeal carcinoma (NPC), MFSD4A-recruited RNF149 mediates the ubiquitination and degradation of EPHA2, thus inhibiting the proliferation, migration, and invasion of NPC cells [11]. Based on TCGA data, RNF149 expression was also significant in many other cancers, including HCC and breast cancer (Figure S1).…”

Genomic and Transcriptomic Characterization of Gastric Cancer with Bone Metastasis

“…TRIM50 encodes an E3 ubiquitin-protein ligase that ubiquitinates Beclin-1/BECN1 to promote autophagy activation, and its RNA expression is enriched in liver and renal cancer [ 26 , 27 ]. In addition, Yang et al [ 28 ] demonstrated that MFSD4A could specifically bind to and degrade EPH receptor A2 (EPHA2), leading to alterations in the PI3K-AKT-ERK1/2 pathway and epithelial-mesenchymal transition, thereby affecting nasopharyngeal carcinoma.…”

LDHA‐mediated M2‐type macrophage polarization via tumor‐derived exosomal EPHA2 promotes renal cell carcinoma progression

“…Through GO enrichment analysis, KEGG pathway enrichment analysis, and literature review, we focused on EPHA2, a protein related to the PI3K/ Akt pathway that affects macrophage polarization after LDHA knockdown (Figure 5C,D). 27,28 F I G U R E 4 (See caption on next page).…”