AEP promotes aberrant RNA splicing through DDX3X cleavage in solid tumors

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.