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

Jorge A Benitez,Webster K Cavenee,Maria Fernanda Camargo,Hrvoje Miletic,Matteo D’Antonio,Shahram Saberi,Alireza Khodadadi-Jamayran,Nathan M Jameson,Jianhui Ma,Ciro Zanca,Frank B Furnari,Kelly A Frazer,Antonia Boyer,Michael Andersen,Stephen Kelly

doi:10.1038/ncomms15223

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.

Highlights

IntroductionGlioblastoma (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
Glioblastoma (GBM) is the most lethal type of human brain cancer, where deletions and mutations in the tumour suppressor gene PTEN are frequent events and are associated with therapeutic resistance
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

Summary

Introduction

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. GBMs undergo genetic lesions that affect the epigenomic machinery that controls histone modifications, DNA methylation and gene expression One such target is the histone H3 variant, H3.3, which is incorporated into chromatin in a cell cycle independent manner and is associated with transcriptionally active and silent chromatin in somatic and embryonic cells[12,13]. DAXX inhibition affects global H3.3 deposition and gene expression, suppresses intracranial tumour growth and significantly improves the survival of PTEN-null glioma-bearing mice. These results demonstrate a synthetic growth defect that occurs due to loss of these two tumour suppressor genes

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Conclusion