期刊
CLINICAL EPIGENETICS
卷 12, 期 1, 页码 -出版社
BMC
DOI: 10.1186/s13148-020-00878-6
关键词
AATK; TP63; DNA methylation; KPC model; Pancreatic cancer
资金
- Ministry of Science and Technology [MOST 105-2320-B-006-018-MY3]
- Hsu-Yuan Education Foundation, Tainan, Taiwan
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 HNF1 alpha. 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 HNF1 alpha allow the proliferation of ductal PanINs in mice. Conclusion Epigenetic silencing ofAATKregulates the cellular transdifferentiation, proliferation, and cell cycle progression in converting PDA-subtypes.
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