Epigenetic modulator inhibition overcomes temozolomide chemoresistance and antagonizes tumor recurrence of glioblastoma
Byoung-San Moon, … , Min Yu, Wange Lu
Byoung-San Moon, … , Min Yu, Wange Lu
Published October 5, 2020
Citation Information: J Clin Invest. 2020;130(11):5782-5799. https://doi.org/10.1172/JCI127916.
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Research Article Oncology Stem cells

Epigenetic modulator inhibition overcomes temozolomide chemoresistance and antagonizes tumor recurrence of glioblastoma

Abstract

Glioblastoma multiforme (GBM) heterogeneity causes a greater number of deaths than any other brain tumor, despite the availability of alkylating chemotherapy. GBM stem-like cells (GSCs) contribute to GBM complexity and chemoresistance, but it remains challenging to identify and target GSCs or factors that control their activity. Here, we identified a specific GSC subset and show that activity of these cells is positively regulated by stabilization of methyl CpG binding domain 3 (MBD3) protein. MBD3 binds to CK1A and to BTRCP E3 ubiquitin ligase, triggering MBD3 degradation, suggesting that modulating this circuit could antagonize GBM recurrence. Accordingly, xenograft mice treated with the CK1A activator pyrvinium pamoate (Pyr-Pam) showed enhanced MBD3 degradation in cells expressing high levels of O6-methylguanine-DNA methyltransferase (MGMT) and in GSCs, overcoming temozolomide chemoresistance. Pyr-Pam blocked recruitment of MBD3 and the repressive nucleosome remodeling and deacetylase (NuRD) complex to neurogenesis-associated gene loci and increased acetyl–histone H3 activity and GSC differentiation. We conclude that CK1A/BTRCP/MBD3/NuRD signaling modulates GSC activation and malignancy, and that targeting this signaling could suppress GSC proliferation and GBM recurrence.

Authors

Byoung-San Moon, Mingyang Cai, Grace Lee, Tong Zhao, Xiaofeng Song, Steven L. Giannotta, Frank J. Attenello, Min Yu, Wange Lu

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Figure 8

MBD3 loss inhibits progression of GBM with either low or high MGMT expression.

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MBD3 loss inhibits progression of GBM with either low or high MGMT expre...
(A–J) pLuc-U118MG cells or pLuc-U251MG cells depleted of MBD3 by shMBD3 or shScramble lentiviral controls were intracranially injected into immunocompromised (NSG) mice. (A–D) Serial bioluminescence imaging was used to monitor tumor volume (each group, n = 5). (B and D) Tumor volume was measured every 3 or 4 days. Quantification (total flux; p/s, photons per second) of the bioluminescent signal from tumor regions in A and C. (E–J) After 4 weeks, mice were sacrificed and analyzed immunohistochemically with the indicated antibodies. Expression of CD133, CD44, CXCR4, and MBD3 (F and I) or Ki67 and nestin (G and J) was quantified using ImageJ software. Images were captured using a Zeiss confocal microscope. Representative images were selected from at least 3 different fields. Data are presented as the mean ± SD. *P < 0.05; **P < 0.005; ***P < 0.0005 by 2-way ANOVA with Bonferroni’s post hoc test (B and D) or unpaired, 2-tailed Student’s t test (F, G, I, and J). Scale bars: 50 μm; and inset scale bars: 50 μm.