PUBLICATION
PP2A methylesterase PME-1 suppresses anoikis and is associated with therapy relapse of PTEN-deficient prostate cancers
- Authors
- Aakula, A., Isomursu, A., Rupp, C., Erickson, A., Gupta, N., Kauko, O., Shah, P., Padzik, A., Pokharel, Y.R., Kaur, A., Li, S.P., Trotman, L., Taimen, P., Rannikko, A., Lammerding, J., Paatero, I., Mirtti, T., Ivaska, J., Westermarck, J.
- ID
- ZDB-PUB-221204-3
- Date
- 2022
- Source
- Molecular Oncology 17(6): 1007-1023 (Journal)
- Registered Authors
- Ivaska, Johanna, Paatero, Ilkka
- Keywords
- AR, Anoikis, ERG, Extracellular matrix, Integrin, LAP2A/B, Nuclear lamina, PP2A-C methylation, PPME1
- MeSH Terms
-
- Animals
- Anoikis*
- Carboxylic Ester Hydrolases*/genetics
- Humans
- Male
- Neoplasm Recurrence, Local
- PTEN Phosphohydrolase/genetics
- Prostatic Neoplasms*/genetics
- Prostatic Neoplasms*/pathology
- Zebrafish
- PubMed
- 36461911 Full text @ Mol. Oncol.
Citation
Aakula, A., Isomursu, A., Rupp, C., Erickson, A., Gupta, N., Kauko, O., Shah, P., Padzik, A., Pokharel, Y.R., Kaur, A., Li, S.P., Trotman, L., Taimen, P., Rannikko, A., Lammerding, J., Paatero, I., Mirtti, T., Ivaska, J., Westermarck, J. (2022) PP2A methylesterase PME-1 suppresses anoikis and is associated with therapy relapse of PTEN-deficient prostate cancers. Molecular Oncology. 17(6):1007-1023.
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 tumors with concomitant inhibition of two tumor suppressor phosphatases, PP2A and PTEN, are particularly aggressive, having less than 50% 5-year secondary-therapy-free patient survival. Functionally, overexpression of PME-1, a methylesterase for the catalytic PP2A-C subunit, inhibits anoikis in PTEN-deficient PCa cells. In vivo, PME-1 inhibition increased apoptosis in in ovo PCa tumor 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.
Genes / Markers
Expression
Phenotype
Mutations / Transgenics
Human Disease / Model
Sequence Targeting Reagents
Fish
Orthology
Engineered Foreign Genes
Mapping