SEC14L4 promotes the development of esophageal squamous cell cancer by inhibiting the ubiquitination and degradation of DDX3X via RNF39

Abstract

Esophageal squamous cell cancer (ESCC) remains an aggressive malignant tumor with limited therapeutic options and poor prognosis. This study aims to uncover novel diagnostic markers and therapeutic targets by investigating molecular drivers of ESCC pathogenesis using integrated omics and functional assays. The gene expression profiles of ESCC tissues were compared with those of normal tissues. SEC14L4 expression was evaluated through qPCR, Western blot, and immunohistochemistry (IHC). Functional roles of SEC14L4 were assessed through cell proliferation, colony formation, apoptosis, migration, and invasion assays. Co-immunoprecipitation (Co-IP) and mass spectrometry were used to discover SEC14L4-interacting proteins. Ubiquitination assays assessed the degradation of DDX3X. The MAPK pathway and ferroptosis markers were analyzed by Western blot to investigate the downstream effects of SEC14L4. In vivo tumor models were used to validate SEC14L4's oncogenic role. SEC14L4 was markedly overexpressed in ESCC tissues, correlating with advanced tumor stage and reduced overall survival. In vitro, SEC14L4 promoted ESCC cell proliferation, migration, and colony formation, while inhibiting apoptosis, while its knockdown reduced these effects. DDX3X overexpression rescued these phenotypes. Co-IP and mass spectrometry confirmed a direct interaction between SEC14L4 and DDX3X, and SEC14L4 was found to inhibit DDX3X ubiquitination via RNF39. SEC14L4 promotes ESCC progression by activating the MAPK signaling pathway and inhibiting ferroptosis. In vivo, SEC14L4 knockdown significantly inhibited tumor growth. SEC14L4 facilitates ESCC development by inhibiting the ubiquitination and degradation of DDX3X by RNF39.