CIC protein instability contributes to tumorigenesis in glioblastoma

Nat Commun. 2019 Feb 8;10(1):661. doi: 10.1038/s41467-018-08087-9.


Capicua (CIC) is a transcriptional repressor that counteracts activation of genes downstream of receptor tyrosine kinase (RTK)/Ras/ERK signaling. It is well-established that tumorigenesis, especially in glioblastoma (GBM), is attributed to hyperactive RTK/Ras/ERK signaling. While CIC is mutated in other tumors, here we show that CIC has a tumor suppressive function in GBM through an alternative mechanism. We find that CIC protein levels are negligible in GBM due to continuous proteasome-mediated degradation, which is mediated by the E3 ligase PJA1 and show that this occurs through binding of CIC to its DNA target and phosphorylation on residue S173. PJA1 knockdown increased CIC stability and extended survival using in-vivo models of GBM. Deletion of the ERK binding site resulted in stabilization of CIC and increased therapeutic efficacy of ERK inhibition in GBM models. Our results provide a rationale to target CIC degradation in Ras/ERK-driven tumors, including GBM, to increase efficacy of ERK inhibitors.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Carcinogenesis / metabolism
  • Carcinogenesis / pathology
  • Cell Line, Tumor
  • Cell Proliferation / genetics
  • Cell Proliferation / physiology
  • Cell Transformation, Neoplastic / metabolism
  • Cell Transformation, Neoplastic / pathology
  • Drosophila
  • Drosophila Proteins / genetics
  • Drosophila Proteins / metabolism
  • Gene Expression Regulation, Developmental / genetics
  • Gene Expression Regulation, Developmental / physiology
  • Glioblastoma / metabolism*
  • Glioblastoma / pathology*
  • HEK293 Cells
  • Humans
  • Male
  • Mice, Inbred C57BL
  • Mice, Transgenic
  • Mutation
  • Repressor Proteins / genetics
  • Repressor Proteins / metabolism*
  • Signal Transduction / genetics
  • Signal Transduction / physiology


  • CIC protein, human
  • Drosophila Proteins
  • Repressor Proteins