KDM6A Regulates Cell Plasticity and Pancreatic Cancer Progression by Noncanonical Activin Pathway

• DOI: 10.1016/j.jcmgh.2021.09.014
• Publication Date: 2021-09-27T15:15:03Z
• Authors: Zhujun Yi; Shanqiao Wei; Lin Jin; Sivakumar Jeyarajan; Jing Yang; Yumei Gu; Hong Sun Kim; Shula Schechter; Shuang Lu; Michelle T. Paulsen; Karan Bedi; Ishwarya Venkata ...; Mats Ljungman; Howard C. Crawford; Marina Pasca di M...; Kai Ge; Yali Dou; Jiaqi Shi
• Keywords: Demethylase; Knockout mouse

Inactivating mutations of KDM6A, a histone demethylase, were frequently found in pancreatic ductal adenocarcinoma (PDAC). We investigated the role KDM6A (lysine demethylase 6A) PDAC development.We performed tissue microarray analysis protein levels. used human cell lines for knockout and knockdown experiments. bromouridine sequencing to elucidate effects loss on global transcription. studies with Ptf1aCre; LSL-KrasG12D; Trp53R172H/+; Kdm6afl/fl or fl/Y, orthotopic xenograft mice investigate impacts Kdm6a deficiency tumorigenesis pancreatitis.Loss was associated metastasis patients. Bromouridine showed up-regulation epithelial-mesenchymal transition pathway cells deficient KDM6A. Loss promoted mesenchymal morphology, migration, invasion vitro. Mechanistically, activin A subsequent p38 activation likely mediated loss. Inhibiting either reversed effect. Pancreas-specific Kdm6a-knockout pancreata accelerated progression, developed more aggressive undifferentiated type PDAC, increased metastases background Kras p53 mutations. Kdm6a-deficient pancreatitis model had delayed recovery precursor lesions compared wild-type pancreata.Loss accelerates progression metastasis, most by noncanonical p38-dependent pathway. also promotes from pancreatitis. Activin might be as therapeutic target KDM6A-deficient PDACs.