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

Xun Jin | Zendy; Hye-Min Jeon | Zendy; Xiong Jin | Zendy; EunJung Kim | Zendy; Jinlong Yin | Zendy; Hee-Young Jeon | Zendy; Young-Woo Sohn | Zendy; Se-Yeong Oh | Zendy; Jun-Kyum Kim | Zendy; Sung-Hak Kim | Zendy; Ji-Eun Jung | Zendy; Sungwook Kwak | Zendy; KaiFu Tang | Zendy; Yunsheng Xu | Zendy; Jeremy N. Rich | Zendy; Hyunggee Kim | Zendy

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

Author(s) -

Xun Jin,

Hye-Min Jeon,

Xiong Jin,

EunJung Kim,

Jinlong Yin,

Hee-Young Jeon,

Young-Woo Sohn,

Se-Yeong Oh,

Jun-Kyum Kim,

Sung-Hak Kim,

Ji-Eun Jung,

Sungwook Kwak,

KaiFu Tang,

Yunsheng Xu,

Jeremy N. Rich,

Hyunggee Kim

Publication year - 2016

Publication title -

cell reports

Language(s) - English

Resource type - Journals

SCImago Journal Rank - 6.264

H-Index - 154

eISSN - 2639-1856

pISSN - 2211-1247

DOI - 10.1016/j.celrep.2016.06.092

Subject(s) - wnt signaling pathway , microbiology and biotechnology , gene knockdown , cancer research , ubiquitin ligase , hek 293 cells , deubiquitinating enzyme , signal transduction , chemistry , ubiquitin , stem cell , fadd , biology , cell culture , apoptosis , programmed cell death , gene , biochemistry , genetics , caspase

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.

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