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

Mai Abdel Mouti, Siwei Deng, Martin Pook, Jessica Malzahn, Aniko Rendek, Stefania Militi, Reshma Nibhani, Zahir Soonawalla, Udo Oppermann, Chang-il Hwang and Siim Pauklin ()
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Mai Abdel Mouti: University of Oxford
Siwei Deng: University of Oxford
Martin Pook: University of Oxford
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

Nature Communications, 2023, vol. 14, issue 1, 1-21

Abstract: 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.

Date: 2023
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DOI: 10.1038/s41467-023-41297-4

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