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Table S4 from Transcription Elongation Machinery Is a Druggable Dependency and Potentiates Immunotherapy in Glioblastoma Stem Cells

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posted on 2023-04-04, 00:03 authored by Zhixin Qiu, Linjie Zhao, Jia Z. Shen, Zhengyu Liang, Qiulian Wu, Kailin Yang, Lihua Min, Ryan C. Gimple, Qiyuan Yang, Shruti Bhargava, Chunyu Jin, Cheryl Kim, Denise Hinz, Deobrat Dixit, Jean A. Bernatchez, Briana C. Prager, Guoxin Zhang, Zhen Dong, Deguan Lv, Xujun Wang, Leo J.Y. Kim, Zhe Zhu, Katherine A. Jones, Ye Zheng, Xiuxing Wang, Jair L. Siqueira-Neto, Lukas Chavez, Xiang-Dong Fu, Charles Spruck, Jeremy N. Rich

Table S4. YY1 expression correlated drug responses in brain cancer cells lines.

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National Cancer Institute Cancer Center

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ARTICLE ABSTRACT

Glioblastoma (GBM) is the most lethal primary brain cancer characterized by therapeutic resistance, which is promoted by GBM stem cells (GSC). Here, we interrogated gene expression and whole-genome CRISPR/Cas9 screening in a large panel of patient-derived GSCs, differentiated GBM cells (DGC), and neural stem cells (NSC) to identify master regulators of GSC stemness, revealing an essential transcription state with increased RNA polymerase II–mediated transcription. The YY1 and transcriptional CDK9 complex was essential for GSC survival and maintenance in vitro and in vivo. YY1 interacted with CDK9 to regulate transcription elongation in GSCs. Genetic or pharmacologic targeting of the YY1–CDK9 complex elicited RNA m6A modification–dependent interferon responses, reduced regulatory T-cell infiltration, and augmented efficacy of immune checkpoint therapy in GBM. Collectively, these results suggest that YY1–CDK9 transcription elongation complex defines a targetable cell state with active transcription, suppressed interferon responses, and immunotherapy resistance in GBM. Effective strategies to rewire immunosuppressive microenvironment and enhance immunotherapy response are still lacking in GBM. YY1-driven transcriptional elongation machinery represents a druggable target to activate interferon response and enhance anti–PD-1 response through regulating the m6A modification program, linking epigenetic regulation to immunomodulatory function in GBM.This article is highlighted in the In This Issue feature, p. 275

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Keywords

Cns Cancers Gliomas, Glioblastomas Epigenetics Gene Regulation Oncogenic transcription factors Immunotherapy Pharmacology Pharmacogenetics/pharmacogenomics Tumor Microenvironment

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