ZCCHC4 regulates esophageal cancer progression and cisplatin resistance through ROS/c-myc axis

Zinc finger CCHC-type containing 4 (ZCCHC4) is a newly discovered N⁶-methyladenosine (m⁶A) RNA methyltransferase (MTase), which possesses an m⁶A MTase domain and an RNA-binding protein (RBP) Znf domain. Aberrantly expressed ZCCHC4 has been found to be correlated with poor prognosis and chemoresistance in various tumors, such as hepatocellular carcinoma, lung cancer and colorectal cancer. However, the expression and functional analysis of the role of ZCCHC4 in esophageal cancer (ESCA) is still elusive. The expression of ZCCHC4 in esophageal cancer tissues was evaluated by qPT-PCR and western blot. Serum esophageal tumor markers are detected by electrochemiluminescence immunoassay. Relationship between ZCCHC4 expression and pathway enrichment analysis were analyzed by R. The reactive oxygen species (ROS), cell proliferation, cell cycle and apoptosis of ZCCHC4 in esophageal squamous cell carcinoma (ESCC) cells tested by CCK8 assay and flow cytometry assay. Aberrant expression of ZCCHC4 is associated with cancer stages, lymph node metastasis (LNM), and tumor histology, and poorer Overall Survival (OS) in esophageal cancer. The mRNA level of ZCCHC4 in esophageal cancer patients correlates with serum carcinoembryonic antigen (CEA) levels, Squamous Cell Carcinoma (SCC) markers, and tissue polypeptide antigen (TPA) levels. Knockdown of ZCCHC4 induces DNA damage, leading to an elevation of reactive oxygen species (ROS), which in turn triggers S-phase arrest, enhances apoptosis, augments sensitivity to cisplatin treatment, and inhibits proliferation in esophageal cancer cells. Conversely, overexpression of ZCCHC4 promotes proliferation, inhibits apoptosis, and increases resistance to cisplatin in esophageal cancer cells. Furthermore, scavenging ROS reverses the effects of ZCCHC4 downregulation on both proliferation and apoptosis in esophageal cancer cells. Additionally, downregulation of ZCCHC4 inhibits the progression of esophageal cancer and reduces cisplatin resistance in vivo. In summary, downregulation of ZCCHC4 leads to increased sensitivity of ESCC cells to cisplatin, inhibits proliferation, and promotes apoptosis in esophageal cancer cells, potentially via the ROS/c-myc axis. The study suggests a potential adjunctive role for ZCCHC4 in the diagnosis and treatment of esophageal cancer and aids in further understanding the underlying mechanisms in ESCA progression.