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BAZ2A association with H3K14ac is required for the dedifferentiation of prostate cancer cells into a cancer stem-like state

Rodrigo Peña-Hernández, Rossana Aprigliano, Sandra Frommel, Karolina Pietrzak, Seraina Steiger, Marcin Roganowicz, Juliana Bizzarro, View ORCID ProfileRaffaella Santoro
doi: https://doi.org/10.1101/2020.07.03.185843
Rodrigo Peña-Hernández
1Department of Molecular Mechanisms of Disease, DMMD, University of Zurich, 8057 Zurich, Switzerland
2Molecular Life Science Program, Life Science Zurich Graduate School, University of Zurich, 8057 Zurich, Switzerland
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Rossana Aprigliano
1Department of Molecular Mechanisms of Disease, DMMD, University of Zurich, 8057 Zurich, Switzerland
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Sandra Frommel
1Department of Molecular Mechanisms of Disease, DMMD, University of Zurich, 8057 Zurich, Switzerland
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Karolina Pietrzak
1Department of Molecular Mechanisms of Disease, DMMD, University of Zurich, 8057 Zurich, Switzerland
2Molecular Life Science Program, Life Science Zurich Graduate School, University of Zurich, 8057 Zurich, Switzerland
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Seraina Steiger
1Department of Molecular Mechanisms of Disease, DMMD, University of Zurich, 8057 Zurich, Switzerland
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Marcin Roganowicz
1Department of Molecular Mechanisms of Disease, DMMD, University of Zurich, 8057 Zurich, Switzerland
2Molecular Life Science Program, Life Science Zurich Graduate School, University of Zurich, 8057 Zurich, Switzerland
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Juliana Bizzarro
1Department of Molecular Mechanisms of Disease, DMMD, University of Zurich, 8057 Zurich, Switzerland
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Raffaella Santoro
1Department of Molecular Mechanisms of Disease, DMMD, University of Zurich, 8057 Zurich, Switzerland
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  • ORCID record for Raffaella Santoro
  • For correspondence: raffaella.santoro@dmmd.uzh.ch
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Abstract

Prostate cancer (PCa) is one of the most prevalent cancers in men. Cancer stem cells are thought to be associated with PCa relapse and represent a target against metastatic PCa. Here we show that BAZ2A (also known as TIP5), a factor previously implicated in aggressive PCa, is required for the dedifferentiation of PCa cells into a cancer stem-like state. We found that BAZ2A genomic occupancy in PCa cells coincides with H3K14ac enriched chromatin regions. This association is mediated by BAZ2A bromodomain (BAZ2A-BRD) that specifically binds to H3K14ac. In PCa cells, BAZ2A-BRD is required for the interaction with a class of inactive enhancers that are marked by H3K14ac and represses transcription of genes implicated in developmental and differentiation processes that are frequently silenced in aggressive and dedifferentiated PCa. BAZ2A-mediated repression of these genes is also linked to the histone acetyltransferase EP300 that acetylates H3K14ac. Mutations of BAZ2A-BRD or treatment with chemical probes that abrogate BAZ2A-BRD association with H3K14ac impair the dedifferentiation of PCa cells into a stem-like state. Furthermore, pharmacological inactivation of BAZ2A-BRD impairs the oncogenic transformation mediated by Pten-loss in prostate organoids. Our findings indicate a role of BAZ2A-BRD in PCa stem cell features and suggest potential epigenetic-reader therapeutic strategies to target BAZ2A in aggressive PCa.

Competing Interest Statement

The authors have declared no competing interest.

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Posted July 04, 2020.
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BAZ2A association with H3K14ac is required for the dedifferentiation of prostate cancer cells into a cancer stem-like state
Rodrigo Peña-Hernández, Rossana Aprigliano, Sandra Frommel, Karolina Pietrzak, Seraina Steiger, Marcin Roganowicz, Juliana Bizzarro, Raffaella Santoro
bioRxiv 2020.07.03.185843; doi: https://doi.org/10.1101/2020.07.03.185843
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BAZ2A association with H3K14ac is required for the dedifferentiation of prostate cancer cells into a cancer stem-like state
Rodrigo Peña-Hernández, Rossana Aprigliano, Sandra Frommel, Karolina Pietrzak, Seraina Steiger, Marcin Roganowicz, Juliana Bizzarro, Raffaella Santoro
bioRxiv 2020.07.03.185843; doi: https://doi.org/10.1101/2020.07.03.185843

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