AEP-cleaved DDX3X induces alternative RNA splicing events to mediate cancer cell adaptation in harsh...

Area of Science:

• Molecular Biology
• Cancer Research
• RNA Splicing

Background:

• Solid tumors often experience oxygen and nutrient deprivation.
• Abnormal alternative splicing (AS) drives tumor progression, but its regulation in harsh tumor microenvironments is unclear.

Purpose of the Study:

• To elucidate the regulatory mechanisms of AS in cancer cell adaptation to hypoxia and nutrient deprivation.
• To identify novel molecular players and pathways involved in tumor malignancy under stress conditions.

Main Methods:

• Investigated hypoxia- and nutrient deprivation-induced cleavage of DDX3X by asparagine endopeptidase (AEP) in a HIF1A-dependent manner.
• Analyzed the nuclear translocation and splicing factor complexation of truncated DDX3X (tDDX3X-C).
• Utilized in vitro assays, glioblastoma organoids, and animal models to assess the role of AEP/tDDX3X-C in tumor progression and patient prognosis.

Main Results:

• AEP cleaves DDX3X into tDDX3X-C, which aggregates in the nucleus and induces aberrant AS events, such as exon skipping in PRDM2.
• The ARRB1-Δexon 13 isoform, generated through this process, regulates glycolysis.
• AEP/tDDX3X-C and ARRB1-Δexon 13 promote tumor malignancy and are associated with poor patient prognosis.

Conclusions:

• Discovered a novel mechanism where AEP-cleaved DDX3X triggers alternative RNA splicing changes, enabling cancer cell adaptation to nutrient and oxygen shortages.
• Identified AEP/tDDX3X-C as a key regulator of tumor adaptation and malignancy.
• Highlighted potential diagnostic and therapeutic targets for solid tumors.