Epigenetic silencing of AATK in acinar to ductal metaplasia in murine model of pancreatic cancer

Li Yun Ding, Ya Chin Hou, I. Ying Kuo, Ting Yi Hsu, Tsung Ching Tsai, Hsiu Wei Chang, Wei Yu Hsu, Chih Chieh Tsao, Chung Chen Tian, Po Shun Wang, Hao Chen Wang, Chung Ta Lee, Yi Ching Wang, Sheng Hsiang Lin, Michael W. Hughes, Woei Jer Chuang, Pei Jung Lu, Yan Shen Shan, Po Hsien Huang

Research output: Contribution to journalArticle

Abstract

Background: Cancer subtype switching, which involves unclear cancer cell origin, cell fate decision, and transdifferentiation of cells within a confined tumor microenvironment, remains a major problem in pancreatic cancer (PDA). Results: By analyzing PDA subtypes in The Cancer Genome Atlas, we identified that epigenetic silencing of apoptosis-associated tyrosine kinase (AATK) inversely was correlated with mRNA expression and was enriched in the quasi-mesenchymal cancer subtype. By comparing early mouse pancreatic lesions, the non-invasive regions showed AATK co-expression in cells with acinar-to-ductal metaplasia, nuclear VAV1 localization, and cell cycle suppression; but the invasive lesions conversely revealed diminished AATK expression in those with poorly differentiated histology, cytosolic VAV1 localization, and co-expression of p63 and HNF1α. Transiently activated AATK initiates acinar differentiation into a ductal cell fate to establish apical-basal polarization in acinar-to-ductal metaplasia. Silenced AATK and ectopically expressed p63 and HNF1α allow the proliferation of ductal PanINs in mice. Conclusion: Epigenetic silencing of AATK regulates the cellular transdifferentiation, proliferation, and cell cycle progression in converting PDA-subtypes.

Original languageEnglish
Article number87
JournalClinical Epigenetics
Volume12
Issue number1
DOIs
Publication statusPublished - 2020 Jun 17

All Science Journal Classification (ASJC) codes

  • Molecular Biology
  • Genetics
  • Developmental Biology
  • Genetics(clinical)

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