PP2A Inactivation Mediated by PPP2R4 Haploinsufficiency Promotes Cancer Development

: Ward Sents, Bob Meeusen, Petar Kalev, Enrico Radaelli, Xavier Sagaert, Eline Miermans, Dorien Haesen, Caroline Lambrecht, Mieke Dewerchin, Peter Carmeliet, Jukka Westermarck, Anna Sablina, Veerle Janssens

Publisher: AMER ASSOC CANCER RESEARCH

: 2017

: Cancer Research

: CANCER RESEARCH

: CANCER RES

: 77

: 24

: 6825

: 6837

: 13

: 0008-5472

DOI: https://doi.org/10.1158/0008-5472.CAN-16-2911

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 PTPA(gt/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(+/g)t 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. (C) 2017 AACR.