TENT5A Maintains MYC mRNA Stability to Enhance Osteosarcoma Stemness

Area of Science:

• Oncology
• Molecular Biology
• RNA Biology

Background:

• MYC amplification drives aggressive osteosarcoma (OS) but shows discordance with its transcriptional output.
• Understanding mechanisms stabilizing MYC is crucial for intercepting persistent MYC signaling in OS.

Purpose of the Study:

• To investigate post-transcriptional mechanisms stabilizing MYC mRNA in osteosarcoma.
• To identify novel therapeutic targets for MYC-driven OS.

Main Methods:

• Multi-omics profiling and single-cell transcriptomics to identify key RNA-binding proteins.
• Biochemical assays and genetic manipulation (gain/loss-of-function) to study TENT5A-MYC mRNA interaction.
• In vivo (orthotopic xenografts) and in vitro (patient-derived organoids) models to assess TENT5A function and therapeutic potential.

Main Results:

• TENT5A, a poly(A) polymerase, is upregulated in MYC-activated OS and binds MYC mRNA, extending its poly(A) tail and enhancing stability.
• Elevated TENT5A promotes stemness, tumor initiation, and chemoresistance in OS models.
• Pharmacologic inhibition of TENT5A reverses MYC mRNA stabilization and chemoresistance.

Conclusions:

• Cytoplasmic mRNA polyadenylation by TENT5A reconciles the MYC copy-number/transcriptional output discordance in OS.
• TENT5A is a critical regulator of MYC-driven stemness and chemoresistance in osteosarcoma.
• TENT5A represents a promising therapeutic target for osteosarcoma treatment.