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

Research output: Contribution to journalArticlepeer-review

42 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.

Original languageEnglish
Pages (from-to)1629-1641
Number of pages13
JournalCell Reports
Volume16
Issue number6
DOIs
Publication statusPublished - 2016 Aug 9

Bibliographical note

Funding Information:
This work was supported by grants from the National Research Foundation of Korea (NRF), funded by the Ministry of Education, Science, and Technology of Korea (2011-0017544), the Korea Health Technology R&D Project through the Korea Health Industry Development Institute (KHIDI), funded by the Ministry of Health & Welfare, Republic of Korea (HI12C1718), and Korea University. J.N.R. is supported by National Institute of Health grants CA154130, CA169117, CA171632, NS087913, and NS089272 and the James S. McDonnel foundation. X.J. was supported by a grant from the General Program of the National Natural Science Foundation of China (no. 81572891). We thank Ji-Hyun Kim (Soonchunhyang University) for providing graphic abstract. We thank Dr. A Soeda for providing GSC1(X01), GSC2(X02), and GSC3(X03) cells.

Publisher Copyright:
© 2016 The Author(s)

Keywords

  • CULLIN3
  • DVL2
  • GLI2
  • ID1
  • glioblastoma stem cells

ASJC Scopus subject areas

  • General Biochemistry,Genetics and Molecular Biology

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