METTL3-mediated m6A modification facilitates Nectin-4-induced VNN1 upregulation and promotion of ESCC progression

Abstract

Esophageal squamous cell carcinoma (ESCC) is a highly aggressive malignancy with poor prognosis and limited therapeutic options. N6-methyladenosine (m6A) RNA modification plays a role in tumorigenesis, but its contributions to ESCC and the regulation of cell adhesion molecules such as Nectin-4 are not fully elucidated. In this study, we investigate the role and the regulatory mechanisms of Nectin-4 in ESCC, particularly regarding the influence of m6A modification and its downstream metabolic effects. Our study demonstrates that methyltransferase-like protein 3 (METTL3) enhances Nectin-4 mRNA stability and expression through m6A methylation in ESCC, as validated by actinomycin D assay, MeRIP-qPCR, and dual-luciferase reporter assay. Both METTL3 and Nectin-4 are highly expressed in ESCC tissues and promote malignant phenotypes such as proliferation, migration, and invasion. Further analysis identifies pantothenate esterase 1 (VNN1) as a downstream target of Nectin-4, mediating the oncogenic effects of the METTL3/Nectin-4 axis and promoting the biosynthesis of pantothenic acid and coenzyme A, thus driving ESCC progression. By integrating transcriptomic data, this study elucidates a key pathogenic mechanism in which the METTL3/Nectin-4/VNN1 axis regulates metabolic reprogramming to promote ESCC development. These findings provide new insights into the molecular pathology of ESCC and offer potential biomarkers and therapeutic targets for early screening, prognosis, and precision treatment for ESSC.

1. Introduction

Esophageal cancer ranks among the most common malignant digestive system tumors globally, with particularly high incidence and mortality rates in China, trailing only behind gastric and colorectal cancers [1]. Despite advances in surgical techniques, radiotherapy, and targeted therapies, the overall 5-year survival rate for esophageal cancer patients remains below 30% [2–4]. This underscores the critical need to thoroughly investigate the pathogenesis of esophageal cancer and identify novel therapeutic targets and strategies to enhance patient outcomes.

N6-methyladenosine (m6A) modification, the most abundant and reversible chemical modification in eukaryotic mRNAs, has emerged as a focal point in epigenetics research due to its crucial role in tumorigenesis and progression through regulation of mRNA metabolism and gene expression [5–9]. To identify key m6A-modified membrane proteins involved in esophageal cancer development, our team conducted an integrated analysis of transcriptome sequencing and MeRIP-seq data from esophageal squamous carcinoma tissues, adjacent normal tissues, and cell lines. This analysis revealed that the cell adhesion molecule Nectin-4 is both highly expressed and undergoes m6A modification in cancer tissues.

Nectin-4, a member of the immunoglobulin superfamily, plays crucial roles in various biological processes, including intercellular adhesion, signal transduction, and viral infection [10,11]. Studies have demonstrated that Nectin-4 is aberrantly expressed in multiple solid tumors, where it promotes malignant processes including cell proliferation, invasion, and metastasis [12–15]. In our investigation of Nectin-4’s role in esophageal cancer development, we confirmed its elevated expression in esophageal cancer cell lines and its ability to promote malignant phenotypes, suggesting that Nectin-4 may serve as both a key driver and potential therapeutic target in esophageal cancer progression.