PP2A methylesterase PME‐1 suppresses anoikis and is associated with therapy relapse of PTEN‐deficient prostate cancers
Abstract
While organ‐confined prostate cancer (PCa) is mostly therapeutically manageable, metastatic progression of PCa remains an unmet clinical challenge. Resistance to anoikis, a form of cell death initiated by cell detachment from the surrounding extracellular matrix, is one of the cellular processes critical for PCa progression towards aggressive disease. Therefore, further understanding of anoikis regulation in PCa might provide therapeutic opportunities. Here, we discover that PCa tumours with concomitant inhibition of two tumour suppressor phosphatases, PP2A and PTEN, are particularly aggressive, having PTEN‐deficient PCa cells. In vivo, PME‐1 inhibition increased apoptosis in in ovo PCa tumour xenografts, and attenuated PCa cell survival in zebrafish circulation. Molecularly, PME‐1‐deficient PC3 cells display increased trimethylation at lysines 9 and 27 of histone H3 (H3K9me3 and H3K27me3), a phenotype known to correlate with increased apoptosis sensitivity. In summary, our results demonstrate that PME‐1 supports anoikis resistance in PTEN‐deficient PCa cells. Clinically, these results identify PME‐1 as a candidate biomarker for a subset of particularly aggressive PTEN‐deficient PCa.
Document Details
- Document Type
- Pub Defense Publication
- Publication Date
- Apr 18, 2023
- Source ID
- 10.1002/1878-0261.13353
Entities
People
- Aleksi Isomursu
- Amanpreet Kaur
- Andrew Erickson
- Anna Aakula
- Antti Rannikko
- Artur Padzik
- Christian Rupp
- Ilkka Paatero
- Jan Lammerding
- Johanna Ivaska
- Jukka Westermarck
- Lloyd Trotman
- Nikhil Gupta
- Otto Kauko
- Pekka Taimen
- Pragya Shah
- Song‐ping Li
- Tuomas Mirtti
- Yuba Raj Pokharel
Organizations
- Cold Spring Harbor Laboratory
- Cornell University
- Finnish Cancer Institute
- National Institutes of Health
- National Science Foundation
- Research Council of Finland
- Turku University Hospital
- United States Department of Defense
- University of Helsinki
- University of Turku