Nowak, D. G., Katsenelson, K. C., Watrud, K. E., Chen, M., Mathew, G., D'Andrea, V. D., Lee, M. F., Swamynathan, M. M., Casanova-Salas, I., Jibilian, M. C., Buckholtz, C. L., Ambrico, A. J., Pan, C. H., Wilkinson, J. E., Newton, A. C., Trotman, L. C.
(May 2019)
The PHLPP2 phosphatase is a druggable driver of prostate cancer progression.
J Cell Biol, 218 (6).
pp. 1943-1957.
ISSN 0021-9525
Abstract
Metastatic prostate cancer commonly presents with targeted, bi-allelic mutations of the PTEN and TP53 tumor suppressor genes. In contrast, however, most candidate tumor suppressors are part of large recurrent hemizygous deletions, such as the common chromosome 16q deletion, which involves the AKT-suppressing phosphatase PHLPP2. Using RapidCaP, a genetically engineered mouse model of Pten/Trp53 mutant metastatic prostate cancer, we found that complete loss of Phlpp2 paradoxically blocks prostate tumor growth and disease progression. Surprisingly, we find that Phlpp2 is essential for supporting Myc, a key driver of lethal prostate cancer. Phlpp2 dephosphorylates threonine-58 of Myc, which renders it a limiting positive regulator of Myc stability. Furthermore, we show that small-molecule inhibitors of PHLPP2 can suppress MYC and kill PTEN mutant cells. Our findings reveal that the frequent hemizygous deletions on chromosome 16q present a druggable vulnerability for targeting MYC protein through PHLPP2 phosphatase inhibitors.
| Item Type: |
Paper
|
| Subjects: |
bioinformatics
bioinformatics > genomics and proteomics > genetics & nucleic acid processing > DNA, RNA structure, function, modification
diseases & disorders
bioinformatics > genomics and proteomics > genetics & nucleic acid processing
bioinformatics > genomics and proteomics
bioinformatics > genomics and proteomics > genetics & nucleic acid processing > DNA, RNA structure, function, modification > genes, structure and function > genes: types > Myc
diseases & disorders > neoplasms
organism description > animal
bioinformatics > genomics and proteomics > genetics & nucleic acid processing > DNA, RNA structure, function, modification > genes, structure and function
bioinformatics > genomics and proteomics > genetics & nucleic acid processing > DNA, RNA structure, function, modification > genes, structure and function > genes: types
organism description > animal > mammal
organism description > animal > mammal > rodent > mouse
bioinformatics > genomics and proteomics > genetics & nucleic acid processing > DNA, RNA structure, function, modification > genes, structure and function > genes: types > oncogene
bioinformatics > genomics and proteomics > genetics & nucleic acid processing > DNA, RNA structure, function, modification > genes, structure and function > genes: types > oncogenes
organs, tissues, organelles, cell types and functions
bioinformatics > genomics and proteomics > genetics & nucleic acid processing > protein structure, function, modification > protein expression > phosphorylation
diseases & disorders > cancer > cancer types > prostate cancer
organism description > animal > mammal > rodent
organs, tissues, organelles, cell types and functions > tissues types and functions > signal transduction
organs, tissues, organelles, cell types and functions > tissues types and functions |
| CSHL Authors: |
Trotman, Lloyd C.
Nowak, Dawid G.
Watrud, Kaitlin
Chen, Muhan
Mathew, Grinu
Lee, Matthew
Casanova Salas, Irene
Ambrico, Alexandra
D'Andrea, Vincent D
Swamynathan, Manojit Mosur
Pan, Chun-Hao
|
| Communities: |
CSHL Cancer Center Program > Cellular Communication in Cancer Program
CSHL labs > Trotman lab
School of Biological Sciences > Publications |
| Depositing User: |
Matthew Dunn
|
| Date: |
15 May 2019 |
| Date Deposited: |
29 May 2019 18:19 |
| Last Modified: |
29 Feb 2024 19:35 |
| PMCID: |
PMC6548123 |
| Related URLs: |
|
| URI: |
https://repository.cshl.edu/id/eprint/37809 |
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