The ID1-CULLIN3 Axis Regulates Intracellular SHH and WNT Signaling in Glioblastoma Stem Cells

Xun Jin, Hye Min Jeon, Xiong Jin, Eun Jung Kim, Jinlong Yin, Hee Young Jeon, Young Woo Sohn, Se Yeong Oh, Jun Kyum Kim, Sung Hak Kim, Ji Eun Jung, Sungwook Kwak, Kai Fu Tang, Yunsheng Xu, Jeremy N. Rich, Hyunggee Kim

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18 Citations (Scopus)

Abstract

Inhibitor of differentiation 1 (ID1) is highly expressed in glioblastoma stem cells (GSCs). However, the regulatory mechanism responsible for its role in GSCs is poorly understood. Here, we report that ID1 activates GSC proliferation, self-renewal, and tumorigenicity by suppressing CULLIN3 ubiquitin ligase. ID1 induces cell proliferation through increase of CYCLIN E, a target molecule of CULLIN3. ID1 overexpression or CULLIN3 knockdown confers GSC features and tumorigenicity to murine . Ink4a/Arf-deficient astrocytes. Proteomics analysis revealed that CULLIN3 interacts with GLI2 and DVL2 and induces their degradation via ubiquitination. Consistent with ID1 knockdown or CULLIN3 overexpression in human GSCs, pharmacologically combined control of GLI2 and β-CATENIN effectively diminishes GSC properties. A ID1-high/CULLIN3-low expression signature correlates with a poor patient prognosis, supporting the clinical relevance of this signaling axis. Taken together, a loss of CULLIN3 represents a common signaling node for controlling the activity of intracellular WNT and SHH signaling pathways mediated by ID1. Jin et al. report that the deregulated proteolysis by ID1-mediated suppression of CULLIN3 controls glioblastoma stem cell proliferation, self-renewal, and tumorigenicity by simultaneously activating intracellular WNT and SHH signaling. The findings provide a rationale for therapeutic intervention targeting multiple intracellular cancer stemness signaling pathways.

Original languageEnglish
JournalCell Reports
DOIs
Publication statusAccepted/In press - 2015 Nov 8

Keywords

  • CULLIN3
  • DVL2
  • GLI2
  • Glioblastoma stem cells
  • ID1

ASJC Scopus subject areas

  • Biochemistry, Genetics and Molecular Biology(all)

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    Jin, X., Jeon, H. M., Jin, X., Kim, E. J., Yin, J., Jeon, H. Y., Sohn, Y. W., Oh, S. Y., Kim, J. K., Kim, S. H., Jung, J. E., Kwak, S., Tang, K. F., Xu, Y., Rich, J. N., & Kim, H. (Accepted/In press). The ID1-CULLIN3 Axis Regulates Intracellular SHH and WNT Signaling in Glioblastoma Stem Cells. Cell Reports. https://doi.org/10.1016/j.celrep.2016.06.092