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19.03.2020 | Laboratory Investigation Open Access

Epigenetic preconditioning with decitabine sensitizes glioblastoma to temozolomide via induction of MLH1

Zeitschrift:
Journal of Neuro-Oncology
Autoren:
Matthew Gallitto, Rossana Cheng He, Julio F. Inocencio, Huaien Wang, Yizhou Zhang, Gintaras Deikus, Isaac Wasserman, Maya Strahl, Melissa Smith, Robert Sebra, Raymund L. Yong
Wichtige Hinweise

Electronic supplementary material

The online version of this article (https://​doi.​org/​10.​1007/​s11060-020-03461-4) contains supplementary material, which is available to authorized users.
Matthew Gallitto and Rossana Cheng He have contributed equally to this work.

Publisher's Note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Abstract

Introduction

To improve the standard treatment paradigm for glioblastoma (GBM), efforts have been made to explore the efficacy of epigenetic agents as chemosensitizers. Recent data suggest possible synergy between decitabine (DAC), a DNA hypomethylating agent, and temozolomide (TMZ) in GBM, but the mechanism remains unclear. The objective of this study was to determine the effects of DAC on TMZ sensitization in a consecutively derived set of primary GBM cultures, with a focus on mismatch repair (MMR) proteins.

Methods

Half maximal inhibitory concentrations (IC50) of TMZ were calculated in eleven consecutive patient-derived GBM cell lines before and after preconditioning with DAC. MMR protein expression changes were determined by quantitative immunoblots and qPCR arrays. Single-molecule real-time (SMRT) sequencing of bisulfite (BS)-converted PCR amplicons of the MLH1 promoter was performed to determine methylation status.

Results

TMZ IC50 significantly changed in 6 of 11 GBM lines of varying MGMT promoter methylation status in response to DAC preconditioning. Knockdown of MLH1 after preconditioning reversed TMZ sensitization. SMRT-BS sequencing of the MLH1 promoter region revealed higher levels of baseline methylation at proximal CpGs in desensitized lines compared to sensitized lines.

Conclusions

DAC enhances TMZ cytotoxicity in a subset of GBM cell lines, comprising lines both MGMT methylated and unmethylated tumors. This effect may be driven by levels of MLH1 via E2F1 transcription factor binding. Using unbiased long-range next-generation bisulfite-sequencing, we identified a region of the proximal MLH1 promoter with differential methylation patterns that has potential utility as a clinical biomarker for TMZ sensitization.

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