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Persistent HCMV infection of a glioblastoma cell line contributes to the development of resistance to temozolomide.

ABSTRACT: Glioblastoma multiforme (GBM) is the most aggressive form of primary human gliomas. While chemotherapy using the DNA alkylating agent temozolomide (TMZ) is a first line treatment for GBMs, the development of resistance to TMZ is a common limitation to successful treatment. Human Cytomegalovirus (HCMV) is a ubiquitous ?-herpesvirus that establishes a lifelong infection latent infection in host haematopoetic cells, where lytic replication of the virus is silenced. HCMV can also establish a persistent infection in hosts, where low levels of virus are lytically produced. Furthermore, multiple studies have identified HCMV DNA and/or proteins in human GBM samples, and have shown that acute infection with HCMV confers a glioblastoma stem cell (GSC) phenotype, further supporting an oncomodulatory role for HCMV in GBM progression and severity. In this current study, we examined the long-term effects of HCMV persistence to cell viability, cell proliferation, and the development of TMZ resistance over time using a glioblastoma cell line known as LN-229. Persistent HCMV infections were established and maintained in this cell line for 30 weeks without the addition of new virus. Here, we report that HCMV persistence in this cell line resulted in increased cell viability, increased cell proliferation, and a marked resistance to the DNA alkylating agent, TMZ, over time, suggesting that low levels of lytically replicating HCMV could contribute to tumor progression in GBM.

SUBMITTER: Singh P

PROVIDER: S-EPMC7357196 | biostudies-literature | 2020 Jan

REPOSITORIES: biostudies-literature

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Persistent HCMV infection of a glioblastoma cell line contributes to the development of resistance to temozolomide.

Singh Pankaj P Neumann Donna M DM

Virus research 20191129

Glioblastoma multiforme (GBM) is the most aggressive form of primary human gliomas. While chemotherapy using the DNA alkylating agent temozolomide (TMZ) is a first line treatment for GBMs, the development of resistance to TMZ is a common limitation to successful treatment. Human Cytomegalovirus (HCMV) is a ubiquitous β-herpesvirus that establishes a lifelong infection latent infection in host haematopoetic cells, where lytic replication of the virus is silenced. HCMV can also establish a persist ...[more]

PMID: 31790777

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Project description:BackgroundDespite the development of new treatment protocols for glioblastoma (GBM), temozolomide (TMZ) resistance remains a primary hindrance. Previous studies, including our study, have shown that aberrant N6-methyladenosine (m6 A) modification is implicated in GBM pathobiology. However, the roles and precise mechanisms of m6 A modification in the regulation of TMZ resistance in GBM remain unclear.Methodsm6 A individual-nucleotide-resolution cross-linking and immunoprecipitation sequencing (miCLIP-seq) was performed to identify m6 A modification of transcripts in TMZ-resistant and -sensitive tumors. To explore the role of METTL3 in TMZ resistance, TMZ-resistant GBM cells were transfected with METTL3 shRNA or overexpression lentivirus and then assessed by cell viability, tumor sphere formation, and apoptosis assays. An intracranial GBM xenograft model was developed to verify the effect of METTL3 depletion during TMZ treatment in vivo. ATAC-seq, ChIP-qPCR, and dual-luciferase reporter assays were carried out to verify the role of SOX4/EZH2 in the modulation of METTL3 expression upon TMZ treatment.ResultsWe demonstrated that TMZ treatment upregulated the expression of the m6 A methyltransferase METTL3, thereby increasing m6 A modification of histone modification-related gene transcripts. METTL3 is required to maintain the features of GBM stem cells. When combined with TMZ, METTL3 silencing suppressed orthotopic TMZ-resistant xenograft growth in a cooperative manner. Mechanistically, TMZ induced a SOX4-mediated increase in chromatin accessibility at the METTL3 locus by promoting H3K27ac levels and recruiting RNA polymerase II. Moreover, METTL3 depletion affected the deposition of m6 A on histone modification-related gene transcripts, such as EZH2, leading to nonsense-mediated mRNA decay. We revealed an important role of EZH2 in the regulation of METTL3 expression, which was via an H3K27me3 modification-independent manner.ConclusionsOur findings uncover the fundamental mechanisms underlying the interplay of m6 A RNA modification and histone modification in TMZ resistance and emphasize the therapeutic potential of targeting the SOX4/EZH2/METTL3 axis in the treatment of TMZ-resistant GBM.

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Persistent HCMV infection of a glioblastoma cell line contributes to the development of resistance to temozolomide.

Publications

Persistent HCMV infection of a glioblastoma cell line contributes to the development of resistance to temozolomide.

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