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PR55α subunit of protein phosphatase 2A supports KRASG12D-driven tumorigenesis that requires YAP activation

Oncogene volume 44, pages 3070–3082 (2025)Cite this article

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Abstract

PP2A holoenzymes account nearly 50% of Ser/Thr phosphatase activities in human cells, yet their roles in oncogenesis remain largely unexplored. A PP2A holoenzyme consists of a catalytic subunit, a scaffold subunit, and a regulatory subunit. We previously reported that PR55α, a PP2A regulatory subunit, supports the tumorigenic and metastatic potential of pancreatic cancer cells, and this is associated with its role in promoting YAP activation, which is essential for tumorigenesis and progression in most solid tumors, including pancreatic cancer. However, the direct role of PR55α in tumorigenesis has not yet been assessed. Using telomerase-immortalized human pancreatic ductal cells (HPNE), this research reveals a mechanism in which PR55α/PP2A cooperates with oncogenic KRASG12D to drive cellular transformation and tumorigenesis in vivo. HPNE-transduced with PR55α and KRASG12D exhibited accelerated proliferation and migration, and anchorage-independent growth, hallmark features of malignant transformation. Biochemical studies demonstrated that PR55α-induced YAP activation was further enhanced by KRASG12D, primarily through the inhibition of the MST/LATS cascade. The essential role of YAP activation in HPNE transformation by PR55α and KRASG12D was confirmed by YAP inhibition. Finally, in vivo studies revealed that HPNE cells transformed by PR55α and KRASG12D were tumorigenic in mice. Collectively, these findings highlight the critical role of PR55α/PP2A in supporting KRAS-driven tumorigenesis, providing new insights into the mechanisms underlying pancreatic cancer progression.

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Fig. 1: Constructing the progressive transformation cellular model system based on normal human pancreatic ductal cells (HPNE).
Fig. 2: PR55α cooperates with oncogenic KRASG12D to increase YAP protein stability.
Fig. 3: Interplay between PR55α and KRASG12D and/or p53R175H in regulating ERK1/2 and MST/LATS signaling.
Fig. 4: The impact of PR55α expression on the morphology, proliferation and motility of HPNE cells in the presence of p53R175H and/or KRASG12D.
Fig. 5: PR55α cooperates with KRASG12D in promoting anchorage-independent growth.
Fig. 6: PR55α cooperates with KRASG12D in promoting tumorigenesis.
Fig. 7: PR55α and YAP are co-overexpressed in human pancreatic PanIN lesions and ductal adenocarcinoma and are positively correlated with poor patient survival.
Fig. 8: The working model of the cooperation of PR55α/PP2A with KRAS signaling in driving tumorigenesis.

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Data availability

The data generated in this study are available within the article and its supplementary files or upon request from the corresponding author on reasonable request. The RNA-sequencing data from the Cancer Genome Atlas database/Pancreatic ductal adenocarcinoma cancer dataset (TCGA-PAAD) [55] was used for analyzing the correlation between PR55α or YAP mRNA expression and PC patient survival (Fig. 7B–D, Supplementary Table S1-S2). The mRNA level (FPKM) > 6.23 was considered high-PR55α expression, and the mRNA level (FPKM) > 19.12 was considered high-YAP expression in the PC specimens. The Kaplan-Meier survival analyses were performed using the online Kaplan-Meier Plotter program (www.kmplot.com) [58].

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Acknowledgements

We thank M.S. Holzapfel and E. Eldridge for assistance with immunohistochemistry analysis in the Tissue Science Core of the University of Nebraska Medical Center. This work was supported, in parts, by grants NIH/R01GM143329 (YY), U.S. Army/USAMRAA/CDMRP/W81XWH-21-1-0700 (YY), a pilot project award from 5U54GM115458 (YY), Nebraska/DHHS (2022-59) (YY), and NIH/R01CA206444 (MMO).

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Author notes

  1. These authors contributed equally: Alison L. Camero, Brendan T. Graff.

Authors and Affiliations

  1. Department of Radiation Oncology, University of Nebraska Medical Center, Omaha, NE, USA

    Christopher B. Jenkins, Alison L. Camero, Brendan T. Graff, Lepakshe S. V. Madduri, Charles A. Enke & Ying Yan

  2. Department of Genetics, Cell Biology, and Anatomy, University of Nebraska Medical Center, Omaha, NE, USA

    Alison L. Camero & Keith R. Johnson

  3. Eppley Institute for Research in Cancer, University of Nebraska Medical Center, Omaha, NE, USA

    Kelly A. O’Connell, Jixin Dong, Michael A. Hollingsworth, Keith R. Johnson & Ying Yan

  4. Department of Pathology and Microbiology, University of Nebraska Medical Center, Omaha, NE, USA

    Ashley L. Hein

  5. Department of Biostatistics, University of Nebraska Medical Center, Omaha, NE, USA

    Lynette M. Smith

  6. Department of Biochemistry and Molecular Biology, University of Nebraska Medical Center, Omaha, NE, USA

    Keith R. Johnson, Michel M. Ouellette & Ying Yan

  7. College of Dentistry-Oral Biology, University of Nebraska Medical Center, Omaha, NE, USA

    Keith R. Johnson

  8. Department of Internal Medicine, University of Nebraska Medical Center, Omaha, NE, USA

    Michel M. Ouellette

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Contributions

C.B.J.: Investigation, data curation, methodology, software, validation, visualization, participating in writing-original draft, writing-review & editing. A.L.C.: Participating in data curation, methodology, review. B.T.G.: Participating in data curation, methodology, review. L.S.V.M.: Participating in data curation, methodology. K.A.O.: Methodology, resources. A.L.H.: Pathology. L.M.S.: Statistics. C.A.E.: Resources, methodology. J.D.: Conceptualization, resources, methodology. M.A.H.: Conceptualization, resources, methodology. K.R.J.: Conceptualization, review-editing. M.M.O.: Resources, conceptualization, methodology, review-editing. Y.Y.: Conceptualization, supervision, Visualization, funding acquisition, project administration, writing-original draft, writing-review-editing.

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Correspondence to Ying Yan.

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All methods in this study were performed in accordance with the relevant guidelines and regulations. Animal care and experimental procedures were reviewed and approved by the University of Nebraska Medical Center-Institutional Animal Care and Use Committee (Protocol # 21-026-05-FC).

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Jenkins, C.B., Camero, A.L., Graff, B.T. et al. PR55α subunit of protein phosphatase 2A supports KRASG12D-driven tumorigenesis that requires YAP activation. Oncogene 44, 3070–3082 (2025). https://doi.org/10.1038/s41388-025-03477-y

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