Journal Article

SATB2 drives glioblastoma growth by recruiting CBP to promote FOXM1 expression in glioma stem cells

Zhang, Aili, Bao, Shideng, Tao, Weiwei, Ahluwalia, Manmeet S, Wu, Qiulian, Fang, Xiaoguang, Rich, Jeremy N, Sloan, Andrew E, Huang, Qian, Lathia, Justin D, Prager, Briana C, Yu, Jennifer S, Huang, Zhi, Zhou, Wenchao, Huang, Haidong, Zhai, Kui, Wang, Xiuxing

2020

Overview

Nuclear matrix‐associated proteins (NMPs) play critical roles in regulating chromatin organization and gene transcription by binding to the matrix attachment regions (MARs) of DNA. However, the functional significance of NMPs in glioblastoma (GBM) progression remains unclear. Here, we show that the Special AT‐rich Binding Protein‐2 (SATB2), one of crucial NMPs, recruits histone acetyltransferase CBP to promote the FOXM1‐mediated cell proliferation and tumor growth of GBM. SATB2 is preferentially expressed by glioma stem cells (GSCs) in GBM. Disrupting SATB2 markedly inhibited GSC proliferation and GBM malignant growth by down‐regulating expression of key genes involved in cell proliferation program. SATB2 activates FOXM1 expression to promote GSC proliferation through binding to the MAR sequence of FOXM1 gene locus and recruiting CBP to the MAR. Importantly, pharmacological inhibition of SATB2/CBP transcriptional activity by the CBP inhibitor C646 suppressed GSC proliferation in vitro and GBM growth in vivo . Our study uncovers a crucial role of the SATB2/CBP‐mediated transcriptional regulation in GBM growth, indicating that targeting SATB2/CBP may effectively improve GBM treatment. SYNOPSIS Aberrant expression of nuclear matrix‐associated proteins (NMPs) has been shown to associate with tumor growth in various human cancers. This study shows that SATB2, a key NMP, and its coactivator CBP critically contribute to glioblastoma (GBM) growth, suggesting SATB2/CBP is a therapeutic target. SATB2 and CBP are preferentially expressed by glioma stem cells (GSCs) in GBMs. SATB2 recruits CBP to activate FOXM1 transcription, promoting GSC proliferation and GBM tumor growth. Inhibition of SATB2/CBP transcriptional activity by the CBP inhibitor C646 suppressed GBM growth. Graphical Abstract Aberrant expression of nuclear matrix‐associated proteins (NMPs) has been shown to associate with tumor growth in various human cancers. This study shows that SATB2, a key NMP, and its coactivator CBP critically contribute to glioblastoma (GBM) growth, suggesting SATB2/CBP is a therapeutic target.

• Publisher: Nature Publishing Group UK,EMBO Press,John Wiley and Sons Inc,Springer Nature
• Subject: Animals / Brain cancer / Brain Neoplasms - genetics / Brain Neoplasms - pathology / Breast cancer / Cancer therapies / CBP / Cell cycle / Cell Line, Tumor / Cell Proliferation / Chromatin / CREB-Binding Protein - metabolism / Deoxyribonucleic acid / DNA / EMBO03 / EMBO09 / EMBO27 / Forkhead Box Protein M1 - genetics / FOXM1 / Gastric cancer / Gene expression / Gene Expression Regulation / Gene Expression Regulation, Neoplastic / Gene regulation / Glioblastoma / Glioblastoma - genetics / Glioblastoma - pathology / Glioma / Glioma cells / glioma stem cell / Histone acetyltransferase / Humans / Liver cancer / Lung cancer / Matrix Attachment Region Binding Proteins - metabolism / Matrix attachment regions / Medical prognosis / Mice / Neoplastic Stem Cells - metabolism / Neoplastic Stem Cells - pathology / Proteins / SATB2 / Stem cells / Transcription / Transcription factors / Transcription Factors - metabolism