Pyruvate dehydrogenase inactivation causes glycolytic phenotype in BAP1 mutant uveal melanoma

Anna Han, Vivian Chua, Usman Baqai, Timothy J. Purwin, Nelisa Bechtel, Emily Hunter, Manoela Tiago, Erin Seifert, David W. Speicher, Zachary T. Schug, J. William Harbour, Andrew E. Aplin

Research output: Contribution to journalArticlepeer-review

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.

Original languageEnglish (US)
Pages (from-to)1129-1139
Number of pages11
JournalOncogene
Volume41
Issue number8
DOIs
StatePublished - Feb 18 2022
Externally publishedYes

ASJC Scopus subject areas

  • Molecular Biology
  • Genetics
  • Cancer Research

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