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Cancer Res. 2017 Dec 15;77(24):6825-6837. doi: 10.1158/0008-5472.CAN-16-2911. Epub 2017 Oct 18.

PP2A Inactivation Mediated by PPP2R4 Haploinsufficiency Promotes Cancer Development.

Author information

1
Laboratory of Protein Phosphorylation and Proteomics, Department of Cellular and Molecular Medicine, KU Leuven, Leuven, Belgium.
2
VIB Center for the Biology of Disease and KU Leuven Department of Oncology, Leuven, Belgium.
3
Translational Cell and Tissue Research, Department of Imaging and Pathology, KU Leuven, Leuven, Belgium.
4
Laboratory of Angiogenesis and Neurovascular Link, Vesalius Research Center, VIB and KU Leuven, Leuven, Belgium.
5
Centre for Biotechnology, University of Turku and Åbo Akademi University, Turku, Finland.
6
LKI, Leuven Cancer Institute, Leuven, Belgium.
7
Laboratory of Protein Phosphorylation and Proteomics, Department of Cellular and Molecular Medicine, KU Leuven, Leuven, Belgium. veerle.janssens@kuleuven.be.

Abstract

Protein phosphatase 2A (PP2A) complexes counteract many oncogenic kinase pathways. In cancer cells, PP2A function can be compromised by several mechanisms, including sporadic mutations in its scaffolding A and regulatory B subunits or more frequently through overexpression of cellular PP2A inhibitors. Here, we identify a novel genetic mechanism by which PP2A function is recurrently affected in human cancer, involving haploinsufficiency of PPP2R4, a gene encoding the cellular PP2A activator PTPA. Notably, up to 70% of cancer patients showed a heterozygous deletion or missense mutations in PPP2R4 Cancer-associated PTPA mutants exhibited decreased abilities to bind the PP2A-C subunit or activate PP2A and failed to reverse the tumorigenic phenotype induced by PTPA suppression, indicating they function as null alleles. In Ppp2r4 gene-trapped (gt) mice showing residual PTPA expression, total PP2A activity and methylation were reduced, selectively affecting specific PP2A holoenzymes. Both PTPAgt/gt and PTPA+/gt mice showed higher rates of spontaneous tumors, mainly hematologic malignancies and hepatocellular adenomas and carcinomas. These tumors exhibited increased c-Myc phosphorylation and increased Wnt or Hedgehog signaling. We observed a significant reduction in lifespan in PTPA+/gt mice compared with wild-type mice. In addition, chemical-induced skin carcinogenesis was accelerated in PTPA+/gt compared with wild-type mice. Our results provide evidence for PPP2R4 as a haploinsufficient tumor suppressor gene, defining a high-penetrance genetic mechanism for PP2A inhibition in human cancer. Cancer Res; 77(24); 6825-37. ©2017 AACR.

PMID:
29046336
DOI:
10.1158/0008-5472.CAN-16-2911
[Indexed for MEDLINE]

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