CHD7 promotes glioblastoma cell motility and invasiveness through transcriptional modulation of an invasion signature

Abstract

Chromatin remodeler proteins exert an important function in promoting dynamic modifications in the chromatin architecture, performing a central role in regulating gene transcription. Deregulation of these molecular machines may lead to striking perturbations in normal cell function. The CHD7 gene is a member of the chromodomain helicase DNA-binding family and, when mutated, has been shown to be the cause of the CHARGE syndrome, a severe developmental human disorder. Moreover, CHD7 has been described to be essential for neural stem cells and it is also highly expressed or mutated in a number of human cancers. However, its potential role in glioblastoma has not yet been tested. Here, we show that CHD7 is up-regulated in human glioma tissues and we demonstrate that CHD7 knockout (KO) in LN-229 glioblastoma cells suppresses anchorage-independent growth and spheroid invasion in vitro . Additionally, CHD7 KO impairs tumor growth and increases overall survival in an orthotopic mouse xenograft model. Conversely, ectopic overexpression of CHD7 in LN-428 and A172 glioblastoma cell lines increases cell motility and invasiveness in vitro and promotes LN-428 tumor growth in vivo . Finally, RNA-seq analysis revealed that CHD7 modulates a specific transcriptional signature of invasion-related target genes. Further studies should explore clinical-translational implications for glioblastoma treatment.

P-selectin axis plays a key role in microglia immunophenotype and glioblastoma progression

“…6B, C). Within these clusters and following differential expression analysis we found genes related to cancer invasion such as Col3a1, Map4k4, Chd7 and Tubb2b [27][28][29] , genes associated with proliferation and tumor progression such as Pdgfa and the oncogenes Fos, Jun and Myc [30][31][32][33] , and angiogenesis genes as VEGFa, Tcf4, Timp1 and Timp3 [34][35][36][37] (Fig. 6D).…”

AN1-type zinc finger protein 3 (ZFAND3) is a transcriptional regulator that drives Glioblastoma invasion

“…Of interest, these three proteins have been previously involved in cell motility in cancer or during development [41][42][43] . Binding sites for ZF containing DNA-binding proteins are enriched in the promoter regions of COL6A2, NRCAM, or FN1, which were previously described in specific invasive signatures in GBM 44,45 . We demonstrate binding of ZFAND3 to the promoter regions of these genes and confirm ZFAND3-induced transcription by dual-reporter gene assays, indicating a role for ZFAND3 in a transcriptional invasion program.…”

Chromatin Imbalance as the Vertex Between Fetal Valproate Syndrome and Chromatinopathies

“…In Table 2, shared pathways with genes deregulated by VPA and downregulated in models of causative genes for KLEFS, KS, CHARGE, MRD1, and ARTHS or ICF1 are summarized (Katsumoto et al, 2006;Issaeva et al, 2007;Min et al, 2007;Fan, 2008;Gupta-Agarwal et al, 2012;Mansour et al, 2012;Balemans et al, 2014;Chen et al, 2014;Kim et al, 2014;Schulz et al, 2014;Turner-Ivey et al, 2014;Gigek et al, 2015;Dhar et al, 2016Dhar et al, , 2018Fang et al, 2016;Mullegama et al, 2016;Sheikh et al, 2016Sheikh et al, , 2017Feng et al, 2017a,b;Shpargel et al, 2017;Whittaker et al, 2017;Baell et al, 2018;Marie et al, 2018;Yao et al, 2018Yao et al, , 2020Carosso et al, 2019;Machado et al, 2019;Nowialis et al, 2019;Cieslar-Pobuda et al, 2020;Frega et al, 2020;Hsu et al, 2020;Kong et al, 2020;Liu et al, 2020;Xu et al, 2020;Ying et al, 2020;Fei et al, 2021;Lopusna et al, 2021). Of note, the most commonly shared pathways involve either morphogenesis signals (for example, beta1 integrin cell surface interactions and extracellular matrix organization), or possible defects of the central nervous system (such as axon guidance and neuro...…”