1. Epigenetically silenced apoptosis-associated tyrosine kinase (AATK) facilitates a decreased expression of Cyclin D1 and WEE1, phosphorylates TP53 and reduces cell proliferation in a kinase-dependent manner.
- Author
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Woods ML, Weiss A, Sokol AM, Graumann J, Boettger T, Richter AM, Schermuly RT, and Dammann RH
- Subjects
- Humans, Cell Cycle Proteins genetics, Cell Cycle Proteins metabolism, Cell Line, Tumor, Cell Proliferation genetics, Cyclin D1 genetics, Tumor Suppressor Protein p53 genetics, Tumor Suppressor Protein p53 metabolism, Pancreatic Neoplasms, Adenocarcinoma, Pancreatic Neoplasms, Protein-Tyrosine Kinases genetics, Protein-Tyrosine Kinases metabolism, Apoptosis Regulatory Proteins genetics, Apoptosis Regulatory Proteins metabolism
- Abstract
Silencing of the Apoptosis associated Tyrosine Kinase gene (AATK) has been described in cancer. In our study, we specifically investigated the epigenetic inactivation of AATK in pancreatic adenocarcinoma, lower grade glioma, lung, breast, head, and neck cancer. The resulting loss of AATK correlates with impaired patient survival. Inhibition of DNA methyltransferases (DNMTs) reactivated AATK in glioblastoma and pancreatic cancer. In contrast, epigenetic targeting via the CRISPR/dCas9 system with either EZH2 or DNMT3A inhibited the expression of AATK. Via large-scale kinomic profiling and kinase assays, we demonstrate that AATK acts a Ser/Thr kinase that phosphorylates TP53 at Ser366. Furthermore, whole transcriptome analyses and mass spectrometry associate AATK expression with the GO term 'regulation of cell proliferation'. The kinase activity of AATK in comparison to the kinase-dead mutant mediates a decreased expression of the key cell cycle regulators Cyclin D1 and WEE1. Moreover, growth suppression through AATK relies on its kinase activity. In conclusion, the Ser/Thr kinase AATK represses growth and phosphorylates TP53. Furthermore, expression of AATK was correlated with a better patient survival for different cancer entities. This data suggests that AATK acts as an epigenetically inactivated tumor suppressor gene., (© 2022. The Author(s).)
- Published
- 2022
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