Functional screen identifies RBM42 as a mediator of oncogenic mRNA translation specificity.

Area of Science:

• Oncology
• Molecular Biology
• Gene Regulation

Background:

• Oncogenic protein levels are critical in cancer development.
• Translational control's role in regulating oncogene dosage, particularly Myc in pancreatic ductal adenocarcinoma (PDAC), is not well understood.
• Myc is a key oncogene driving PDAC progression.

Purpose of the Study:

• To identify factors that activate selective translation of the Myc oncogene in PDAC.
• To elucidate the mechanisms by which translational control contributes to oncogenesis.

Main Methods:

• A CRISPR interference screen was employed in PDAC cells to identify MYC translation activators.
• RNA-binding protein RBM42 was identified as a top hit.
• In vivo studies were conducted to assess RBM42's role in PDAC tumorigenesis.

Main Results:

• The RNA-binding protein RBM42 was identified as a key activator of MYC translation.
• RBM42 is highly expressed in PDAC and correlates with poor patient survival.
• RBM42 selectively enhances the translation of MYC, JUN, and EGFR by remodeling the MYC 5' untranslated region.
• RBM42 is essential for Myc-dependent PDAC tumorigenesis in vivo.

Conclusions:

• RBM42 plays a critical role in regulating oncogenic protein translation in PDAC.
• Targeting RBM42 may offer a novel therapeutic strategy for pancreatic cancer.
• This study advances the understanding of translational control in cancer biology.