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

Jorge A. Benitez, Jianhui Ma, Matteo D’Antonio, Antonia Boyer, Maria Fernanda Camargo, Ciro Zanca, Stephen Kelly, Alireza Khodadadi-Jamayran, Nathan M. Jameson, Michael Andersen, Hrvoje Miletic, Shahram Saberi, Kelly A. Frazer, Webster K. Cavenee () and Frank B. Furnari ()
Additional contact information
Jorge A. Benitez: Ludwig Institute for Cancer Research
Jianhui Ma: Ludwig Institute for Cancer Research
Matteo D’Antonio: The Moores Cancer Center, University of California San Diego
Antonia Boyer: Ludwig Institute for Cancer Research
Maria Fernanda Camargo: The Moores Cancer Center, University of California San Diego
Ciro Zanca: Ludwig Institute for Cancer Research
Stephen Kelly: Laura & Isaac Perlmutter Cancer Center, and The Helen L. and Martin S. Kimmel Center for Stem Cell Biology, NYU School of Medicine
Alireza Khodadadi-Jamayran: Laura & Isaac Perlmutter Cancer Center, and The Helen L. and Martin S. Kimmel Center for Stem Cell Biology, NYU School of Medicine
Nathan M. Jameson: Ludwig Institute for Cancer Research
Michael Andersen: Haukeland University Hospital
Hrvoje Miletic: Haukeland University Hospital
Shahram Saberi: University of California, San Diego
Kelly A. Frazer: The Moores Cancer Center, University of California San Diego
Webster K. Cavenee: Ludwig Institute for Cancer Research
Frank B. Furnari: Ludwig Institute for Cancer Research

Nature Communications, 2017, vol. 8, issue 1, 1-15

Abstract: 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.

Date: 2017
References: Add references at CitEc
Citations: View citations in EconPapers (1)

Downloads: (external link)
https://www.nature.com/articles/ncomms15223 Abstract (text/html)

Related works:
This item may be available elsewhere in EconPapers: Search for items with the same title.

Export reference: BibTeX RIS (EndNote, ProCite, RefMan) HTML/Text

Persistent link: https://EconPapers.repec.org/RePEc:nat:natcom:v:8:y:2017:i:1:d:10.1038_ncomms15223

Ordering information: This journal article can be ordered from
https://www.nature.com/ncomms/

DOI: 10.1038/ncomms15223

Access Statistics for this article

Nature Communications is currently edited by Nathalie Le Bot, Enda Bergin and Fiona Gillespie

More articles in Nature Communications from Nature
Bibliographic data for series maintained by Sonal Shukla () and Springer Nature Abstracting and Indexing ().