American Association for Cancer Research
00085472can180342-sup-196444_2_supp_4739044_p8cswc.pdf (5.32 MB)

Figure S4 from The Tumor Suppressor CIC Directly Regulates MAPK Pathway Genes via Histone Deacetylation

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journal contribution
posted on 2023-03-31, 01:44 authored by Simon Weissmann, Paul A. Cloos, Simone Sidoli, Ole N. Jensen, Steven Pollard, Kristian Helin

Supplementary Figure S4 depicts global gene expression changes in G144 cells (WT and CIC-KO) in response to MEK inhibition as well as expression changes after HDAC inhibition in combination with MEK inhibition at selected target genes.


Danish National Research Foundation

Brain Tumour Charity

European Research Council

Novo Nordisk Foundation



Oligodendrogliomas are brain tumors accounting for approximately 10% of all central nervous system cancers. CIC is a transcription factor that is mutated in most patients with oligodendrogliomas; these mutations are believed to be a key oncogenic event in such cancers. Analysis of the Drosophila melanogaster ortholog of CIC, Capicua, indicates that CIC loss phenocopies activation of the EGFR/RAS/MAPK pathway, and studies in mammalian cells have demonstrated a role for CIC in repressing the transcription of the PEA3 subfamily of ETS transcription factors. Here, we address the mechanism by which CIC represses transcription and assess the functional consequences of CIC inactivation. Genome-wide binding patterns of CIC in several cell types revealed that CIC target genes were enriched for MAPK effector genes involved in cell-cycle regulation and proliferation. CIC binding to target genes was abolished by high MAPK activity, which led to their transcriptional activation. CIC interacted with the SIN3 deacetylation complex and, based on our results, we suggest that CIC functions as a transcriptional repressor through the recruitment of histone deacetylases. Independent single amino acid substitutions found in oligodendrogliomas prevented CIC from binding its target genes. Taken together, our results show that CIC is a transcriptional repressor of genes regulated by MAPK signaling, and that ablation of CIC function leads to increased histone acetylation levels and transcription at these genes, ultimately fueling mitogen-independent tumor growth.Significance: Inactivation of CIC inhibits its direct repression of MAPK pathway genes, leading to their increased expression and mitogen-independent growth.Graphical Abstract: Cancer Res; 78(15); 4114–25. ©2018 AACR.

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