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Modulating BAP1 expression affects ROS homeostasis, cell motility and mitochondrial function

Lucie Hebert1, Dorine Bellanger1, Chloé Guillas1

  • 1Department of Genetics and Biology of Cancers, INSERM U830, Institut Curie, PSL Research University, Paris 75248, France.

Oncotarget
|October 27, 2017
PubMed

Insights

The BAP1 tumor suppressor protein stabilizes other proteins via its deubiquitinase activity, impacting cytoskeleton, mitochondria, and ROS levels. This proteomic approach reveals novel BAP1 functions in cancer.

Area of Science:

  • Biochemistry
  • Molecular Biology
  • Cancer Research

Background:

  • The BAP1 (BRCA1-associated protein 1) gene product is a key component of the PR-DUB complex, involved in histone modification and protein deubiquitination.
  • Despite its role in a Polycomb complex, transcriptional changes are not consistently observed in BAP1-inactivated tumors, suggesting alternative mechanisms of tumor suppression.
  • BAP1's tumor suppressor activity may involve protein stabilization through its deubiquitinase function, independent of canonical transcriptional regulation.

Purpose of the Study:

  • To investigate the functional consequences of BAP1 inactivation and its deubiquitinase activity on cellular proteomes and pathways.
  • To explore the hypothesis that BAP1 stabilizes proteins, thereby exerting its tumor suppressor functions.
  • To identify novel cellular and tumorigenic roles of BAP1 and validate proteomic analysis as a readout for BAP1 inactivation.

Main Methods:

  • Quantitative mass spectrometry was employed to analyze protein expression changes.
  • Gene expression arrays were used to assess transcriptomic alterations.
  • Functional assays were performed in mesothelioma cell lines with varying BAP1 expression (inactivated, wild-type, catalytically dead).

Main Results:

  • Proteomic analysis revealed significant alterations in cytoskeleton organization, mitochondrial activity, and reactive oxygen species (ROS) management upon BAP1 modulation.
  • Gene expression profiling indicated enrichment in the epithelial-to-mesenchymal transition (EMT) pathway.
  • Functional studies confirmed that BAP1's deubiquitinase activity is essential for maintaining these cellular phenotypes, and ROS modulation partially restored cellular functions.

Conclusions:

  • BAP1 plays a crucial role in regulating cellular morphology, mitochondrial function, and ROS homeostasis, likely through its protein stabilization activity.
  • BAP1's deubiquitinase activity is mandatory for maintaining these cellular phenotypes, highlighting a non-transcriptional mechanism of tumor suppression.
  • Proteomic profiling offers a valuable approach to understanding the impact of BAP1 inactivation in cancer and identifying novel therapeutic targets.
Keywords:
BAP1de-ubiquitinationprotein stabilityproteomicstumor suppressor

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