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Updated: Jul 16, 2025

Studying Pancreatic Cancer Stem Cell Characteristics for Developing New Treatment Strategies
07:29

Studying Pancreatic Cancer Stem Cell Characteristics for Developing New Treatment Strategies

Published on: June 20, 2015

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KMT2A associates with PHF5A-PHF14-HMG20A-RAI1 subcomplex in pancreatic cancer stem cells and epigenetically regulates

Mai Abdel Mouti1, Siwei Deng1, Martin Pook1,2

  • 1Botnar Research Centre, Nuffield Department of Orthopaedics, Rheumatology, and Musculoskeletal Sciences, University of Oxford, Oxford, UK.

Nature Communications
|September 14, 2023
PubMed

Insights

Pancreatic cancer stem cells (PCSCs) drive tumor relapse due to their self-renewal capabilities. Targeting KMT2A, an epigenetic regulator, with a KMT2A-WDR5 inhibitor reduces PCSC self-renewal and tumor growth.

Area of Science:

  • Oncology
  • Epigenetics
  • Cancer Stem Cell Biology

Background:

  • Pancreatic cancer (PC) is highly aggressive and resistant to chemotherapy.
  • Pancreatic cancer stem cells (PCSCs) contribute to treatment resistance and tumor relapse.
  • The molecular mechanisms sustaining PCSC properties remain largely unknown.

Purpose of the Study:

  • To identify molecular mechanisms regulating pancreatic cancer stem cell (PCSC) properties.
  • To investigate the role of epigenetic regulators in PCSC maintenance.
  • To evaluate the therapeutic potential of targeting identified regulators in pancreatic cancer.

Main Methods:

  • Proteomic analysis to identify binding partners of RNA polymerase-associated complexes.
  • Chromatin immunoprecipitation and functional assays to characterize epigenetic regulation.
  • In vitro and in vivo studies using PCSC models and KMT2A-WDR5 inhibitors.

Main Results:

  • Identified KMT2A as a binding partner of the PHF5A-PHF14-HMG20A-RAI1 protein subcomplex.
  • Demonstrated KMT2A's role as an epigenetic regulator of PCSC self-renewal and viability.
  • Showed that KMT2A-WDR5 inhibition significantly reduced PCSC self-renewal, cell viability, and in vivo tumorigenicity.

Conclusions:

  • KMT2A is a key epigenetic regulator of pancreatic cancer stem cell functions.
  • Targeting the KMT2A-WDR5 interaction presents a promising therapeutic strategy for pancreatic cancer.
  • Inhibition of KMT2A may overcome chemoresistance mediated by PCSCs.

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