American Association for Cancer Research
00085472can130109-sup-supfig_1-5_suptab_1-5.pdf (1.53 MB)

Supplementary Figures 1-5 and Tables 1-5 from Chromatin Regulator PRC2 Is a Key Regulator of Epigenetic Plasticity in Glioblastoma

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journal contribution
posted on 2023-03-30, 21:42 authored by Atsushi Natsume, Motokazu Ito, Keisuke Katsushima, Fumiharu Ohka, Akira Hatanaka, Keiko Shinjo, Shinya Sato, Satoru Takahashi, Yuta Ishikawa, Ichiro Takeuchi, Hiroki Shimogawa, Motonari Uesugi, Hideyuki Okano, Seung U. Kim, Toshihiko Wakabayashi, Jean-Pierre J. Issa, Yoshitaka Sekido, Yutaka Kondo

PDF - 157KB, Figure S1. Characterization of GSCs. Figure S2. Significance of EZH2/PRC2 in GBMs and GSCs. Figure S3. ChIP-chip analysis and MCAM analysis in GSCs. Figure S4. Effects of Wnt1-KD and BMP5-overexpression in GSCs. Figure S5. Downregulation of EZH2 abrogates tumorigenicity. Supplementary Table S1. Primer sequence data Supplementary Table S2. Tumorigenicity of GSCs and S-BTCs in the brain of NOD-SCID mice Supplementary Table S3. Validation of microarray analyses Supplementary Table S4. Targets of H3K27me3 in 1228-GSC, 1228-S-BTC, 0316-GSC, and 0316-S-BTC Supplementary Table S5. List of genes with commonly altered expression in 1228- and 0316-GSCs after serum exposure.



Tumor cell plasticity contributes to functional and morphologic heterogeneity. To uncover the underlying mechanisms of this plasticity, we examined glioma stem-like cells (GSC) where we found that the biologic interconversion between GSCs and differentiated non-GSCs is functionally plastic and accompanied by gain or loss of polycomb repressive complex 2 (PRC2), a complex that modifies chromatin structure. PRC2 mediates lysine 27 trimethylation on histone H3 and in GSC it affected pluripotency or development-associated genes (e.g., Nanog, Wnt1, and BMP5) together with alterations in the subcellular localization of EZH2, a catalytic component of PRC2. Intriguingly, exogenous expression of EZH2-dNLS, which lacks nuclear localization sequence, impaired the repression of Nanog expression under differentiation conditions. RNA interference (RNAi)–mediated attenuation or pharmacologic inhibition of EZH2 had little to no effect on apoptosis or bromodeoxyuridine incorporation in GSCs, but it disrupted morphologic interconversion and impaired GSC integration into the brain tissue, thereby improving survival of GSC-bearing mice. Pathologic analysis of human glioma specimens revealed that the number of tumor cells with nuclear EZH2 is larger around tumor vessels and the invasive front, suggesting that nuclear EZH2 may help reprogram tumor cells in close proximity to this microenvironment. Our results indicate that epigenetic regulation by PRC2 is a key mediator of tumor cell plasticity, which is required for the adaptation of glioblastoma cells to their microenvironment. Thus, PRC2-targeted therapy may reduce tumor cell plasticity and tumor heterogeneity, offering a new paradigm for glioma treatment. Cancer Res; 73(14); 4559–70. ©2013 AACR.

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