Abstract
Protein Phosphatase 2A (PP2A) enzymes counteract diverse kinase-driven oncogenic pathways and their function is frequently impaired in cancer. PP2A inhibition is indispensable for full transformation of human cells, but whether loss of PP2A is sufficient for tumorigenesis in vivo has remained elusive. Here, we describe spontaneous tumor development in knockout mice for Ppp2r5d, encoding the PP2A regulatory B56δ subunit. Several primary tumors were observed, most commonly, hematologic malignancies and hepatocellular carcinomas (HCCs). Targeted immunoblot and immunohistochemistry analysis of the HCCs revealed heterogeneous activation of diverse oncogenic pathways known to be suppressed by PP2A-B56. RNA sequencing analysis unveiled, however, a common role for oncogenic c-Myc activation in the HCCs, independently underscored by c-Myc Ser62 hyperphosphorylation. Upstream of c-Myc, GSK-3β Ser9 hyperphosphorylation occurred both in the HCCs and non-cancerous B56δ-null livers. Thus, uncontrolled c-Myc activity due to B56δ-driven GSK-3β inactivation is the likely tumor predisposing factor. Our data provide the first compelling mouse genetics evidence sustaining the tumor suppressive activity of a single PP2A holoenzyme, constituting the final missing incentive for full clinical development of PP2A as cancer biomarker and therapy target.
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Acknowledgements
We thank Y El-Aalamat (KU Leuven, ESAT) for help with statistical analysis, and P Vermaelen (KU Leuven, MOSAIC) for PET-scan analysis. Funding was provided by KU Leuven Research Fund (GOA/08/016 to VJ; OT/13/094 to VJ and AS), Research Foundation-Flanders (G.0582.11 to VJ; G.0B01.16N to VJ), Belgian IAP program (P7/13 to VJ), Flemish Agency for Innovation by Science and Technology (to CL) and the Flemish Cancer League (Emmanuel van der Schueren fellowship to WS).
Author contributions
CL performed all mouse-related and immunoblot experiments, analyzed the data and prepared manuscript figures. WS and JVL assisted CL in several mouse-related experiments (dissections, genotyping). LL, XS and PP performed histopathologic analyses. YH and JC performed RNAseq sample preparation and data analysis (IPA, iRegulon). AS analyzed data, co-supervised the study and revised the manuscript. VJ analyzed the data, supervised the study and wrote the manuscript.
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Lambrecht, C., Libbrecht, L., Sagaert, X. et al. Loss of protein phosphatase 2A regulatory subunit B56δ promotes spontaneous tumorigenesis in vivo. Oncogene 37, 544–552 (2018). https://doi.org/10.1038/onc.2017.350
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DOI: https://doi.org/10.1038/onc.2017.350
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