Deoxyhypusine hydroxylase: A novel therapeutic target differentially expressed in short-term vs long-term survivors of glioblastoma

Paula Ofek, Eilam Yeini, Gali Arad, Artem Danilevsky, Sabina Pozzi, Christian Burgos Luna, Sahar Israeli Dangoor, Rachel Grossman, Zvi Ram, Noam Shomron, Henry Brem, Thomas M. Hyde, Tamar Geiger, Ronit Satchi-Fainaro*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

2 Scopus citations

Abstract

Glioblastoma (GB) is the most aggressive neoplasm of the brain. Poor prognosis is mainly attributed to tumor heterogeneity, invasiveness and drug resistance. Only a small fraction of GB patients survives longer than 24 months from the time of diagnosis (ie, long-term survivors [LTS]). In our study, we aimed to identify molecular markers associated with favorable GB prognosis as a basis to develop therapeutic applications to improve patients' outcome. We have recently assembled a proteogenomic dataset of 87 GB clinical samples of varying survival rates. Following RNA-seq and mass spectrometry (MS)-based proteomics analysis, we identified several differentially expressed genes and proteins, including some known cancer-related pathways and some less established that showed higher expression in short-term (<6 months) survivors (STS) compared to LTS. One such target found was deoxyhypusine hydroxylase (DOHH), which is known to be involved in the biosynthesis of hypusine, an unusual amino acid essential for the function of the eukaryotic translation initiation factor 5A (eIF5A), which promotes tumor growth. We consequently validated DOHH overexpression in STS samples by quantitative polymerase chain reaction (qPCR) and immunohistochemistry. We further showed robust inhibition of proliferation, migration and invasion of GB cells following silencing of DOHH with short hairpin RNA (shRNA) or inhibition of its activity with small molecules, ciclopirox and deferiprone. Moreover, DOHH silencing led to significant inhibition of tumor progression and prolonged survival in GB mouse models. Searching for a potential mechanism by which DOHH promotes tumor aggressiveness, we found that it supports the transition of GB cells to a more invasive phenotype via epithelial-mesenchymal transition (EMT)-related pathways.

Original languageEnglish
Pages (from-to)654-668
Number of pages15
JournalInternational Journal of Cancer
Volume153
Issue number3
DOIs
StatePublished - 1 Aug 2023

Funding

FundersFunder number
ERC Proof of Concept
InSightec
Morris Kahn Foundation
NICO Myriad Corporation
PoC862580, 3DCanPredict
National Institutes of Health
National Cancer Institute20150909
Israel Cancer Research FundPROF‐18‐682
Johns Hopkins University
Naomi Foundation
Clade Therapeutics
European Research Council835227
Israel Science Foundation1969/18

    Keywords

    • deoxyhypusine hydroxylase (DOHH)
    • glioblastoma
    • long-term survivors
    • proteogenomics
    • short-term survivors

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