Yi Z, Wei S, Jin L, Jeyarajan S, Yang J, Gu Y, Kim HS, Schechter S, Lu S, Paulsen MT, Bedi K, Narayanan IV, Ljungman M, Crawford HC, Pasca di Magliano M, Ge K, Dou Y, and Shi J. KDM6A Regulates Cell Plasticity and Pancreatic Cancer Progression by Non-Canonical Activin Pathway. Cell Mol Gastroenterol Hepatol 2021.
Cell Mol Gastroenterol Hepatol
BACKGROUND & AIMS: Inactivating mutations of KDM6A, a histone demethylase, were frequently found in pancreatic ductal adenocarcinoma (PDAC). We investigated the role of KDM6A in PDAC development.
METHODS: We performed a pancreatic tissue microarray analysis of KDM6A protein levels. We used human PDAC cell lines for KDM6A knockout and knockdown experiments. We performed Bru-seq analysis to elucidate the effects of KDM6A loss on global transcription. We performed studies with Ptf1a(Cre); LSL-Kras(G12D); Trp53(R172H/+); Kdm6a(fl/fl or fl/Y), Ptf1a(Cre); Kdm6a(fl/fl or fl/Y), and orthotopic xenograft mice to investigate the impacts of Kdm6a deficiency on pancreatic tumorigenesis and pancreatitis.
RESULTS: Loss of KDM6A was associated with metastasis in PDAC patients. Bru-seq analysis revealed upregulation of the epithelial-mesenchymal transition pathway in PDAC cells deficient of KDM6A. Loss of KDM6A promoted mesenchymal morphology, migration, and invasion in PDAC cells in vitro. Mechanistically, activin A and subsequent p38 activation likely mediated the role of KDM6A loss. Inhibiting either activin A or p38 reversed the effect. Pancreas-specific Kdm6a-knockout mice pancreata demonstrated accelerated PDAC progression, developed a more aggressive undifferentiated type PDAC, and increased metastases in the background of Kras and p53 mutations. Kdm6a-deficient pancreata in a pancreatitis model had a delayed recovery with increased PDAC precursor lesions compared to wild-type pancreata.
CONCLUSIONS: Loss of KDM6A accelerates PDAC progression and metastasis, most likely by a non-canonical p38-dependant activin A pathway. KDM6A also promotes pancreatic tissue recovery from pancreatitis. Activin A might be utilized as a therapeutic target for KDM6A-deficient PDACs.
ePub ahead of print