The tumor suppressor CIC directly regulates MAPK pathway genes via histone deacetylation

Simon Weissmann, Paul A. Cloos, Simone Sidoli, Ole N. Jensen, Steven Pollard, Kristian Helin

Research output: Contribution to journalArticle

3 Citations (Scopus)

Abstract

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.

Original languageEnglish (US)
Pages (from-to)4114-4125
Number of pages12
JournalCancer Research
Volume78
Issue number15
DOIs
StatePublished - Aug 1 2018
Externally publishedYes

Fingerprint

Histones
Oligodendroglioma
Genes
Neoplasms
Sin3 Histone Deacetylase and Corepressor Complex
Transcription Factors
Histone Deacetylases
Amino Acid Substitution
Acetylation
Drosophila melanogaster
Mitogens
Brain Neoplasms
Transcriptional Activation
Cell Cycle
Central Nervous System
Cell Proliferation
Genome
Mutation
Growth

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

Cite this

The tumor suppressor CIC directly regulates MAPK pathway genes via histone deacetylation. / Weissmann, Simon; Cloos, Paul A.; Sidoli, Simone; Jensen, Ole N.; Pollard, Steven; Helin, Kristian.

In: Cancer Research, Vol. 78, No. 15, 01.08.2018, p. 4114-4125.

Research output: Contribution to journalArticle

Weissmann, Simon ; Cloos, Paul A. ; Sidoli, Simone ; Jensen, Ole N. ; Pollard, Steven ; Helin, Kristian. / The tumor suppressor CIC directly regulates MAPK pathway genes via histone deacetylation. In: Cancer Research. 2018 ; Vol. 78, No. 15. pp. 4114-4125.
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