American Association for Cancer Research
10780432ccr123066-sup-f3_pdf_4m.pdf (4.23 MB)

Supplementary Figure 3 from Inhibition of BET Bromodomain Targets Genetically Diverse Glioblastoma

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journal contribution
posted on 2023-03-31, 18:18 authored by Zhixiang Cheng, Yuanying Gong, Yufang Ma, Kaihua Lu, Xiang Lu, Larry A. Pierce, Reid C. Thompson, Susanne Muller, Stefan Knapp, Jialiang Wang

PDF file - 4 MB, (A) Reduced expression of BRD2, BRD3, BRD4 following expression of corresponding shRNA sequences was determined by qRT-PCR in T4302 CD133+ cells. Cell growth was measured for 5 days following knockdown of (B) BRD2, (C) BRD3, or (D) BRD4 in T4302 CD133+ cells as described in Figure 2A.



Purpose: Glioblastoma is refractory to conventional therapies. The bromodomain and extraterminal domain (BET) proteins are epigenetic readers that selectively bind to acetylated lysine residues on histone tails. These proteins recently emerged as important therapeutic targets in NUT midline carcinoma and several types of hematopoietic cancers. In this study, the therapeutic potential of a novel BET bromodomain inhibitor, JQ1, was assessed in a panel of genetically heterogeneous glioblastoma samples.Experimental Design: The antineoplastic effects of JQ1 were shown using ex vivo cultures derived from primary glioblastoma xenograft lines and surgical specimens of different genetic background. The in vivo efficacy was assessed in orthotopic glioblastoma tumors.Results: We showed that JQ1 induced marked G1 cell-cycle arrest and apoptosis, which was phenocopied by knockdown of individual BET family members. JQ1 treatment resulted in significant changes in expression of genes that play important roles in glioblastoma such as c-Myc, p21CIP1/WAF1, hTERT, Bcl-2, and Bcl-xL. Unlike the observations in some hematopoietic cancer cell lines, exogenous c-Myc did not significantly protect glioblastoma cells against JQ1. In contrast, ectopically expressed Bcl-xL partially rescued cells from JQ1-induced apoptosis, and knockdown of p21CIP1/WAF1 attenuated JQ1-induced cell-cycle arrest. Cells genetically engineered for Akt hyperactivation or p53/Rb inactivation did not compromise JQ1 efficacy, suggesting that these frequently mutated signaling pathways may not confer resistance to JQ1. Furthermore, JQ1 significantly repressed growth of orthotopic glioblastoma tumors.Conclusion: Our results suggest potentially broad therapeutic use of BET bromodomain inhibitors for treating genetically diverse glioblastoma tumors. Clin Cancer Res; 19(7); 1748–59. ©2013 AACR.

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