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

Oncogene volume 45, pages 999–1012 (2026) Cite this article

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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.

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Fig. 1: Characterization and prognostic value of SEC14L4 in ESCC.
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Fig. 2: Effect of shSEC14L4 on the viability, colony formation, apoptosis, and invasiveness of ESCC cells.
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Fig. 3: SEC14L4 and DDX3X interaction in KYSE450 cells.
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Fig. 4: Effects of DDX3X knockdown on the biological functions of ESCC cells.
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Fig. 5: Impact of SEC14L4 knockdown and DDX3X overexpression on the viability, colony formation, migration, and invasion of ESCC cells.
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Fig. 6: SEC14L4 affects DDX3X stability by regulating RNF39-mediated ubiquitination.
The alternative text for this image may have been generated using AI.
Fig. 7: SEC14L4 activates the MAPK pathway and inhibits ferroptosis through DDX3X.
The alternative text for this image may have been generated using AI.
Fig. 8: Suppression of KYSE450 tumor growth by SEC14L4 knockdown in vivo.
The alternative text for this image may have been generated using AI.

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Data availability

The datasets generated and analysed during the current study are available at the China National GeneBank (https://ngdc.cncb.ac.cn/gsa-human/browse/HRA013457).

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Funding

This work was supported by the National Natural Science Foundation of China (82303497, 82373010) and the special scientific research project of tumor Immunity of Wu Jie-ping Medical Foundation (HIM-2024-0483).

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Author notes

  1. These authors contributed equally: Dayu Huang, Dongdong Wang, Youbo Wang.

Authors and Affiliations

  1. Department of Thoracic Surgery, Huashan Hospital Affiliated to Fudan University, Shanghai, PR China

    Dayu Huang, Youbo Wang, Xuan Wang, Chang He, Qinyun Ma, Xiaofeng Chen & An Wang

  2. Department of Radiology, Huashan Hospital Affiliated to Fudan University, Shanghai, PR China

    Dongdong Wang

  3. Department of Emergency, Huashan Hospital Affiliated to Fudan University, Shanghai, PR China

    Yu Du

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  1. Dayu Huang
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Contributions

DH: Writing-original draft, Writing-review and editing, Investigation, Validation, Formal analysis and Conceptualization. DW: Writing-review and editing, Investigation, Data curation and Validation. YW: Writing-review and editing, Investigation, Data curation and Validation. XW: Project Administration, Funding Acquisition. CH: Writing-review and editing, Investigation, Validation. YD: Writing-review and editing, Investigation, Validation. QM: Resources, Project administration and Supervision. XC: Resources, Project administration, Funding acquisition and Supervision. AW: Resources, Project administration, Funding acquisition and Supervision. All authors read and approved the final manuscript.

Corresponding authors

Correspondence to Qinyun Ma, Xiaofeng Chen or An Wang.

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Competing interests

The authors declare no competing interests.

Ethics approval and consent to participate

The study has been approved by the Ethics Committee of Huashan Hospital Affiliated to Fudan University, and all study participants signed an informed consent (2024-452). It has passed animal review by Department of Laboratory Animal Science of Fudan University (2024-HSYY-546). All experiments were performed in accordance with protocol and guidelines approved by our institution.

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Informed consent was obtained from all individual participants included in the study. All authors have read and approved the final version of the manuscript.

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Huang, D., Wang, D., Wang, Y. et al. SEC14L4 promotes the development of esophageal squamous cell cancer by inhibiting the ubiquitination and degradation of DDX3X via RNF39. Oncogene 45, 999–1012 (2026). https://doi.org/10.1038/s41388-026-03700-4

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