2. Academic Validation
  3. KMT2A associates with PHF5A-PHF14-HMG20A-RAI1 subcomplex in pancreatic cancer stem cells and epigenetically regulates their characteristics

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

  • Nat Commun. 2023 Sep 14;14(1):5685. doi: 10.1038/s41467-023-41297-4.
Mai Abdel Mouti 1,  Siwei Deng 1,  Martin Pook 1 2,  Jessica Malzahn 1,  Aniko Rendek 3,  Stefania Militi 1,  Reshma Nibhani 1,  Zahir Soonawalla 4,  Udo Oppermann 1,  Chang-Il Hwang 5,  Siim Pauklin 6
Affiliations

Affiliations

  • 1 Botnar Research Centre, Nuffield Department of Orthopaedics, Rheumatology, and Musculoskeletal Sciences, University of Oxford, Oxford, UK.
  • 2 Institute of Biomedicine and Translational Medicine, Faculty of Medicine, University of Tartu, Tartu, Estonia.
  • 3 Department of Histopathology, Oxford University Hospitals NHS Foundation Trust, Oxford, UK.
  • 4 Department of Hepatobiliary and Pancreatic Surgery, Oxford University Hospitals NHS, Oxford, UK.
  • 5 Department of Microbiology and Molecular Genetics, University of California Davis, Davis, USA.
  • 6 Botnar Research Centre, Nuffield Department of Orthopaedics, Rheumatology, and Musculoskeletal Sciences, University of Oxford, Oxford, UK. [email protected].
PMID: 37709746 DOI: 10.1038/s41467-023-41297-4
Abstract

Pancreatic Cancer (PC), one of the most aggressive and life-threatening human malignancies, is known for its resistance to cytotoxic therapies. This is increasingly ascribed to the subpopulation of undifferentiated cells, known as pancreatic Cancer Stem Cells (PCSCs), which display greater evolutionary fitness than other tumor cells to evade the cytotoxic effects of chemotherapy. PCSCs are crucial for tumor relapse as they possess 'stem cell-like' features that are characterized by self-renewal and differentiation. However, the molecular mechanisms that maintain the unique characteristics of PCSCs are poorly understood. Here, we identify the Histone Methyltransferase KMT2A as a physical binding partner of an RNA polymerase-associated PHF5A-PHF14-HMG20A-RAI1 protein subcomplex and an epigenetic regulator of PCSC properties and functions. Targeting the protein subcomplex in PCSCs with a KMT2A-WDR5 inhibitor attenuates their self-renewal capacity, cell viability, and in vivo tumorigenicity.

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