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Nat Commun. 2017 May 12;8:15223. doi: 10.1038/ncomms15223.

PTEN regulates glioblastoma oncogenesis through chromatin-associated complexes of DAXX and histone H3.3.

Author information

1
Ludwig Institute for Cancer Research, La Jolla, California 92093-0660, USA.
2
The Moores Cancer Center, University of California San Diego, La Jolla, California 92093, USA.
3
Department of Pediatrics and Rady Children's Hospital, University of California San Diego, La Jolla, California 92093, USA.
4
Sanford Consortium for Regenerative Medicine, University of California, San Diego, 3855 Health Science Drive, La Jolla, California 92037, USA.
5
Department of Pathology, Laura &Isaac Perlmutter Cancer Center, and The Helen L. and Martin S. Kimmel Center for Stem Cell Biology, NYU School of Medicine, New York, New York 10016, USA.
6
Center for Health Informatics and Bioinformatics, NYU School of Medicine, New York, New York 10016, USA.
7
Department of Pathology, Haukeland University Hospital, 5021 Bergen, Norway.
8
Department of Biomedicine, University of Bergen, 5009 Bergen, Norway.
9
KG Jebsen Brain Tumour Research Center, University of Bergen, 5009 Bergen, Norway.
10
Department of Neurosciences, University of California, San Diego, La Jolla, California 92093, USA.
11
Institute for Genomic Medicine, University of California San Diego, La Jolla, California 92093, USA.
12
Department of Pathology, University of California San Diego, La Jolla, California 92093, USA.

Abstract

Glioblastoma (GBM) is the most lethal type of human brain cancer, where deletions and mutations in the tumour suppressor gene PTEN (phosphatase and tensin homolog) are frequent events and are associated with therapeutic resistance. Herein, we report a novel chromatin-associated function of PTEN in complex with the histone chaperone DAXX and the histone variant H3.3. We show that PTEN interacts with DAXX and, in turn PTEN directly regulates oncogene expression by modulating DAXX-H3.3 association on the chromatin, independently of PTEN enzymatic activity. Furthermore, DAXX inhibition specifically suppresses tumour growth and improves the survival of orthotopically engrafted mice implanted with human PTEN-deficient glioma samples, associated with global H3.3 genomic distribution changes leading to upregulation of tumour suppressor genes and downregulation of oncogenes. Moreover, DAXX expression anti-correlates with PTEN expression in GBM patient samples. Since loss of chromosome 10 and PTEN are common events in cancer, this synthetic growth defect mediated by DAXX suppression represents a therapeutic opportunity to inhibit tumorigenesis specifically in the context of PTEN deletion.

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