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Updated: Jul 4, 2025

Engineering Artificial Factors to Specifically Manipulate Alternative Splicing in Human Cells
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Engineering Artificial Factors to Specifically Manipulate Alternative Splicing in Human Cells

Published on: April 26, 2017

9.0K

AEP promotes aberrant RNA splicing through DDX3X cleavage in solid tumors

Yadong Xie, Haohao Zhang, Xinyang Song

    The Journal of Clinical Investigation
    |February 1, 2024
    PubMed

    Insights

    Aberrant RNA splicing in solid tumors is promoted by asparagine endopeptidase (AEP). Tumor microenvironments activate AEP, which alters RNA splicing via DDX3X, suggesting AEP as a therapeutic target.

    Area of Science:

    • Molecular Biology
    • Cancer Research
    • Biochemistry

    Background:

    • Aberrant alternative splicing (AS) is common in cancers.
    • Somatic mutations and RNA-binding proteins (RBPs) are linked to AS and malignancy.
    • Upstream mechanisms driving cancer-associated AS remain largely unknown.

    Purpose of the Study:

    • To identify upstream mechanisms regulating aberrant alternative splicing in solid tumors.
    • To elucidate the role of asparagine endopeptidase (AEP) in cancer-associated AS.
    • To investigate the functional link between AEP, DDX3X, and tumor progression.

    Main Methods:

    • Investigated the activity of asparagine endopeptidase (AEP) under tumor microenvironment conditions.
    • Utilized hypoxia-inducible factor 1-alpha (HIF1A) dependency assays.
    • Examined the cleavage of RNA helicase DDX3X by AEP.
    • Analyzed DDX3X nuclear retention and its interaction with splicing machinery.
    • Assessed AS events in cancer cells.

    Main Results:

    • Tumor environmental factors (oxygen/nutrient deprivation) activate AEP in a HIF1A-dependent manner.
    • Activated AEP cleaves DDX3X, promoting its nuclear retention.
    • Nuclear DDX3X interacts with splicing machinery to induce aberrant AS events in cancer cells.
    • AEP-dependent AS contributes to solid tumor progression.

    Conclusions:

    • Asparagine endopeptidase (AEP) plays a critical role in promoting aberrant RNA splicing in solid tumors.
    • AEP activation by tumor microenvironment factors drives AS through DDX3X cleavage and nuclear retention.
    • Targeting the AEP-dependent aberrant RNA splicing cascade offers a potential therapeutic strategy for solid tumors.

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