The PHLPP2 phosphatase is a druggable driver of prostate cancer progression

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

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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:	Publisher
URI:	https://repository.cshl.edu/id/eprint/37809

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