Splicing factor TRA2A contributes to esophageal cancer progression via a noncanonical role in lncRNA m⁶ A methylation

Area of Science:

• Molecular Biology
• Oncology
• Epigenetics

Background:

• Transformer 2 alpha homolog (TRA2A) is a splicing factor involved in development and cancer.
• Its role in long noncoding RNA (lncRNA) regulation, particularly in esophageal cancer, is not well understood.

Purpose of the Study:

• To investigate the function of TRA2A in esophageal cancer (ESCA).
• To explore TRA2A's role in lncRNA regulation and its impact on cancer progression.

Main Methods:

• Epitranscriptomic microarray, MeRIP-qPCR, RNA pull-down, and CLIP analyses to assess lncRNA methylation and stability.
• Co-immunoprecipitation (Co-IP) to identify protein interactions.
• Xenograft nude mouse models to evaluate tumor growth.
• Virtual screening and cellular thermal shift assays to identify potential therapeutic compounds.

Main Results:

• TRA2A is upregulated in ESCA and correlates with poor prognosis.
• TRA2A depletion reduces global lncRNA methylation and specifically decreases m6A modification of the oncogenic lncRNA MALAT1, leading to reduced stability.
• TRA2A interacts with METTL3 and RBMX, influencing KIAA1429 expression.
• Knockdown of TRA2A inhibits cancer cell proliferation, which can be restored by RBMX/KIAA1429 overexpression.
• Nebivolol, an FDA-approved drug, was identified as a potential inhibitor of TRA2A-MALAT1 interaction and esophageal cancer cell proliferation.

Conclusions:

• TRA2A plays a noncanonical role in ESCA by coordinating with methylation proteins to promote oncogenic MALAT1.
• TRA2A, MALAT1, RBMX, and KIAA1429 are identified as prognostic factors for ESCA.
• Nebivolol shows potential as a therapeutic agent for esophageal cancer by targeting the TRA2A-MALAT1 axis.