Master regulators governing protein abundance across ten human cancer types

Area of Science:

• Molecular Biology
• Genomics
• Proteomics
• Cancer Biology

Background:

• Protein abundance is only moderately correlated with mRNA levels.
• Post-transcriptional regulation by ribosomes, RNA-binding proteins (RBPs), and the proteasome modulates protein levels.
• Understanding these regulatory networks is crucial for deciphering gene expression and cancer development.

Purpose of the Study:

• To identify Master Protein abundance Regulators (MaPRs) across ten cancer types.
• To analyze the role of MaPRs in post-transcriptional regulatory networks and cancer-specific vulnerabilities.
• To validate the findings through experimental evidence.

Main Methods:

• Development of a computational pipeline to jointly analyze transcriptomes and proteomes from 1,305 tumor samples.
• Identification of MaPRs based on network connectivity, genetic dependency, and enrichment for RBPs.
• Integration of tumor up-regulation, druggability, and target network analyses.
• Validation using eCLIP binding and knockdown assays.

Main Results:

• Identified 232 to 1,394 MaPRs per cancer type, mediating up to 79% of post-transcriptional regulatory networks.
• MaPRs exhibit high network connectivity, genetic dependency in cancer cells, and are enriched for RBPs.
• Discovered cancer-specific vulnerabilities by combining tumor up-regulation, druggability, and network analyses.
• MaPRs predicted tumor proteomic subtypes more accurately than other proteins.
• Validated RBP MaPR-target relationships through experimental evidence.

Conclusions:

• MaPRs are central regulators governing post-transcriptional networks in human proteome regulation.
• These findings highlight the diverse processes underlying proteome regulation and identify key regulators in cancer biology.
• MaPRs represent potential therapeutic targets for cancer treatment.