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A super-enhancer-regulated RNA-binding protein cascade drives pancreatic cancer

Corina E Antal1,2,3, Tae Gyu Oh1,4, Stefan Aigner5

  • 1Gene Expression Laboratory, Salk Institute for Biological Studies, La Jolla, CA, 92037, USA.

Nature Communications
|September 6, 2023
PubMed

Insights

Researchers discovered a druggable RNA-binding protein cascade in pancreatic cancer (PDAC) that enhances tumor growth by boosting mRNA translation. Inhibiting this pathway shows promise for treating PDAC, especially in Myc-high cases.

Area of Science:

  • Oncology
  • Molecular Biology
  • Epigenetics

Background:

  • Pancreatic ductal adenocarcinoma (PDAC) is a deadly cancer requiring novel therapies.
  • Super-enhancers (SEs) identify key genes driving cell-specific functions.
  • RNA-binding proteins (RBPs) play critical roles in gene regulation.

Purpose of the Study:

  • To identify novel therapeutic targets in PDAC by analyzing SE-associated gene networks.
  • To investigate the role of RBPs in PDAC growth and mRNA translation.
  • To explore the potential of targeting the RBP cascade for PDAC treatment.

Main Methods:

  • Unbiased analysis of super-enhancers (SEs) in PDAC.
  • Identification and characterization of an RBP cascade involving hnRNP-F, PRMT1, and UAP2L.
  • Functional studies in PDAC patient organoids and mouse models.
  • Pharmacological inhibition of PRMT1.

Main Results:

  • A druggable SE-mediated RBP cascade essential for PDAC growth was uncovered.
  • This cascade enhances PDAC growth through increased mRNA translation.
  • PRMT1 inhibition demonstrated efficacy in Myc-high PDAC organoids and reduced tumor growth in mice.
  • The Myc oncogene was found to coordinately regulate the identified SE and RBP genes.

Conclusions:

  • A functional link between epigenetic regulation (SEs) and mRNA translation in PDAC was established.
  • The identified RBP cascade represents a novel therapeutic vulnerability in PDAC.
  • Targeting PRMT1 offers a promising strategy for PDAC treatment, particularly in Myc-driven tumors.

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