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

Author

Listed:
  • Mai Abdel Mouti

    (University of Oxford)

  • Siwei Deng

    (University of Oxford)

  • Martin Pook

    (University of Oxford
    University of Tartu)

  • Jessica Malzahn

    (University of Oxford)

  • Aniko Rendek

    (Oxford University Hospitals NHS Foundation Trust)

  • Stefania Militi

    (University of Oxford)

  • Reshma Nibhani

    (University of Oxford)

  • Zahir Soonawalla

    (Oxford University Hospitals NHS)

  • Udo Oppermann

    (University of Oxford)

  • Chang-il Hwang

    (University of California Davis)

  • Siim Pauklin

    (University of Oxford)

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.

Suggested Citation

  • Mai Abdel Mouti & Siwei Deng & Martin Pook & Jessica Malzahn & Aniko Rendek & Stefania Militi & Reshma Nibhani & Zahir Soonawalla & Udo Oppermann & Chang-il Hwang & Siim Pauklin, 2023. "KMT2A associates with PHF5A-PHF14-HMG20A-RAI1 subcomplex in pancreatic cancer stem cells and epigenetically regulates their characteristics," Nature Communications, Nature, vol. 14(1), pages 1-21, December.
    • Handle: RePEc:nat:natcom:v:14:y:2023:i:1:d:10.1038_s41467-023-41297-4
    DOI: 10.1038/s41467-023-41297-4
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    Cited by:

    1. Chao-Hui Chang & Feng Liu & Stefania Militi & Svenja Hester & Reshma Nibhani & Siwei Deng & James Dunford & Aniko Rendek & Zahir Soonawalla & Roman Fischer & Udo Oppermann & Siim Pauklin, 2024. "The pRb/RBL2-E2F1/4-GCN5 axis regulates cancer stem cell formation and G0 phase entry/exit by paracrine mechanisms," Nature Communications, Nature, vol. 15(1), pages 1-29, December.

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