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

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.

HPAanalyze: An R Package that Facilitates the Retrieval and Analysis of The Human Protein Atlas Data

“…However, a recently published study demonstrated that PTEN also forms complexes with the histone chaperone DAXX and the histone variant H3.3, modulating chromatin association to regulate oncogene expression. This effect is independent of PTEN enzymatic activity (13). Congruent with these data, we noted that PTEN was present in both the cytosol and the nucleus ( Figure 3C).…”

Expanding the Known Functional Repertoire of the Human Cytomegalovirus pp71 Protein

“…As HCMV seropositivity increases with age (Bate et al, 2010), perhaps pp71-mediated inactivation of Daxx precludes the need for mutation of this pathway in adults with HCMVpositive tumors. Recently, Daxx and the Phosphatase and Tensin homolog (PTEN) tumor suppressor were shown to have a synthetic lethal relationship in GBMs, where Daxx knockdown impaired tumor growth in PTEN-negative but not PTENpositive tumor cells (Benitez et al, 2017). Thus, it would be interesting to determine whether there is an inverse relationship between HCMV-positivity and PTEN mutation in adult GBMs.…”

The Personalisation of Glioblastoma Treatment Using Whole Exome Sequencing: A Pilot Study

“…Variants in the PTEN gene could also be useful in the personalisation of GBM treatment as mentioned previously; Han et al established a relationship between PTEN mutations and GBM patient survival [13]. Jiang et al demonstrated that PTEN mutations are associated with therapeutic resistance [31]; while Benitez et al demonstrated that PTEN regulates GBM oncogenesis [32]. Mutations in the PIK3R1gene have been shown to promote the growth and formation of gliomas [33], while PIK3CA missense mutations have been shown to promote GBM pathogenesis [34].…”