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Pyruvate dehydrogenase inactivation causes glycolytic phenotype in BAP1 mutant uveal melanoma

Oncogene volume 41, pages 1129–1139 (2022)Cite this article

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Abstract

Effective therapeutic options are still lacking for uveal melanoma (UM) patients who develop metastasis. Metastatic traits of UM are linked to BRCA1-associated protein 1 (BAP1) mutations. Cell metabolism is re-programmed in UM with BAP1 mutant UM, but the underlying mechanisms and opportunities for therapeutic intervention remain unclear. BAP1 mutant UM tumors have an elevated glycolytic gene expression signature, with increased expression of pyruvate dehydrogenase (PDH) complex and PDH kinase (PDHK1). Furthermore, BAP1 mutant UM cells showed higher levels of phosphorylated PDHK1 and PDH that was associated with an upregulated glycolytic profile compared to BAP1 wild-type UM cells. Suppressing PDHK1-PDH phosphorylation decreased glycolytic capacity and cell growth, and induced cell cycle arrest of BAP1 mutant UM cells. Our results suggest that PDHK1-PDH phosphorylation is a causative factor of glycolytic phenotypes found in BAP1 mutant UM and propose a therapeutic opportunity for BAP1 mutant UM patients.

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Fig. 1: BAP1 mutant UM tumors have elevated mRNA levels related to PDC and PDHK1.
Fig. 2: BAP1 mutant UM cells have elevated PDHK1-PDH phosphorylation.
Fig. 3: BAP1 mutant UM cells have increased glycolytic profiles.
Fig. 4: Suppression of PDH phosphorylation decreased the glycolytic capacity of BAP1 mutant UM cells.
Fig. 5: Inhibition of PDH phosphorylation reduces cell survival of BAP1 mutant UM cells.
Fig. 6: Suppression of PDH phosphorylation leads to the cell cycle arrest in BAP1 mutant UM cells.
Fig. 7: UM patient survival curve based on PDC and PDHK1 expression.

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Acknowledgements

The Cancer Center Support Grant 5P30CA056036-17 to the SKCC supported the Microscopy Shared Resource facility. We thank Dr. Bruce Ksander (Schepens Eye Research Institute, Boston, MA), Dr. Martine Jager (Leiden University, Leiden, The Netherlands), and Dr. Sergio Roman-Roman (Institute Curie, Paris, France) for cell lines. We are grateful to Dr. Michael Durante (University of Miami Miller School of Medicine, Miami, FL) for his help with single-cell RNA-Seq data and Dr. Hsin-Yao Tang (The Wistar Institute, Philadelphia, PA) for metabolomic analyses. This work was supported by National Institutes of Health (NIH)/National Cancer Institute (NCI) grants R01 CA196278, R01 CA253977, and P01 CA114046 to AEA. This work also was supported by a Melanoma Research Alliance team science award (#559058) to AEA and JWH. The Wistar Proteomics and Metabolomics Facility was supported by P30CA010815, P01CA140043, and S10OD023586. Further support was from the American Association for Cancer Research (AACR)/Ocular Melanoma Foundation (OMF) awarded to AH.

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  1. These authors contributed equally: Anna Han, Vivian Chua.

Authors and Affiliations

  1. Department of Cancer Biology, Thomas Jefferson University, Philadelphia, PA, 19107, USA

    Anna Han, Vivian Chua, Usman Baqai, Timothy J. Purwin, Nelisa Bechtel, Emily Hunter, Manoela Tiago & Andrew E. Aplin

  2. Department of Food Science and Human Nutrition, Jeonbuk National University, Jeonju, Jeollabuk-do, 54896, Republic of Korea

    Anna Han

  3. Department of Pathology, Thomas Jefferson University, Philadelphia, PA, 19107, USA

    Erin Seifert

  4. Proteomics and Metabolomics Facility, The Wistar Institute, Philadelphia, PA, 19104, USA

    David W. Speicher

  5. Molecular and Cellular Oncogenesis Program, The Wistar Institute, Philadelphia, PA, 19104, USA

    David W. Speicher & Zachary T. Schug

  6. Bascom Palmer Eye Institute, Sylvester Comprehensive Cancer Center and Interdisciplinary Stem Cell Institute, University of Miami Miller School of Medicine, Miami, FL, 33146, USA

    J. William Harbour

  7. Department of Ophthalmology, Harold C. Simmons Comprehensive Cancer Center, UT Southwestern Medical Center, Dallas, TX, 75390, USA

    J. William Harbour

  8. Sidney Kimmel Cancer Center, Thomas Jefferson University, Philadelphia, PA, 19107, USA

    Andrew E. Aplin

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Contributions

Conceptualization: AH; Formal analysis: AH, UB, and TJP; Investigations and interpretations: AH, TJP, UB, NB, VC, EH, MT, and ZTS; Resources: AH, ES, DWS, and JWH; Writing (original draft): AH; Writing (review and editing): AH, VC, UB, ES, ZTS, DWS JWH, and AEA; Funding acquisition: AH, DWS, JWH, and AEA; Supervision: AEA.

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Correspondence to Andrew E. Aplin.

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Competing interests

AEA reports receiving a commercial research grant from Pfizer Inc. (2013–2017) and has ownership interest in patent number 9880150. JWH is the inventor of intellectual property related to prognostic testing for uveal melanoma. He is a paid consultant for Castle Biosciences, licensee of this intellectual property, and he receives royalties from its commercialization. The other authors disclose no potential conflicts of interest.

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Han, A., Chua, V., Baqai, U. et al. Pyruvate dehydrogenase inactivation causes glycolytic phenotype in BAP1 mutant uveal melanoma. Oncogene 41, 1129–1139 (2022). https://doi.org/10.1038/s41388-021-02154-0

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