Transcriptome-wide RNA Stability Across Cancers Reveals Therapeutic Vulnerabilities

Area of Science:

• Molecular Biology
• Cancer Biology
• Genomics

Background:

• Steady-state mRNA levels depend on transcription and degradation.
• The role of RNA stability in cancer remains unclear.
• Post-transcriptional regulation is key in cancer development.

Purpose of the Study:

• Investigate RNA decay dynamics across diverse cancer types.
• Identify molecular subtypes based on RNA stability.
• Explore the role of RNA-binding proteins (RBPs) and microRNAs (miRNAs) in cancer RNA stability.

Main Methods:

• Systematic analysis of RNA-seq data from the Cancer Cell Line Encyclopedia.
• Inference of transcriptome-wide RNA stability profiles.
• Integrative analyses of RBPs, miRNAs, and somatic mutations.
• Machine learning models to predict drug sensitivity.

Main Results:

• Identified distinct cancer subtypes defined by RNA stability.
• RBPs (e.g., SNRPA, RBMX) and miRNAs are key modulators of RNA stability and cancer cell survival.
• Somatic mutations affecting miRNA binding sites disrupt RNA decay.
• RNA stability profiles predict sensitivity to 24 anticancer drugs.

Conclusions:

• RNA stability is a critical regulatory layer in cancer.
• RNA stability profiles have implications for molecular stratification.
• RBPs are potential biomarkers for predicting therapeutic response in precision oncology.