title: The ID1-CULLIN3 Axis Regulates Intracellular SHH and WNT Signaling in Glioblastoma Stem Cells.
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.
authors.affiliation: Department of Biotechnology, College of Life Sciences and Biotechnology, Korea University, Seoul 02841, Republic of Korea; Department of Stem Cell Biology and Regenerative Medicine, Lerner Research Institute, Cleveland Clinic, Cleveland, OH 44195, USA; First Affiliated Hospital of Wenzhou Medical University, Wenzhou 325015, Zhejiang, P.R. China; Tianjin Medical University Cancer Institute and Hospital, Tianjin 300060, P.R. China.
authors.forename: Xun
authors.initials: X
authors.lastname: Jin
authors.affiliation: Department of Biotechnology, College of Life Sciences and Biotechnology, Korea University, Seoul 02841, Republic of Korea.
authors.forename: Hye-Min
authors.initials: HM
authors.lastname: Jeon
authors.affiliation: Department of Biotechnology, College of Life Sciences and Biotechnology, Korea University, Seoul 02841, Republic of Korea.
authors.forename: Xiong
authors.initials: X
authors.lastname: Jin
authors.affiliation: Department of Biotechnology, College of Life Sciences and Biotechnology, Korea University, Seoul 02841, Republic of Korea.
authors.forename: Eun-Jung
authors.initials: EJ
authors.lastname: Kim
authors.affiliation: Specific Organs Cancer Division, Research Institute and Hospital, National Cancer Center, Goyang 10408, Republic of Korea.
authors.forename: Jinlong
authors.initials: J
authors.lastname: Yin
authors.affiliation: Department of Biotechnology, College of Life Sciences and Biotechnology, Korea University, Seoul 02841, Republic of Korea.
authors.forename: Hee-Young
authors.initials: HY
authors.lastname: Jeon
authors.affiliation: Department of Biotechnology, College of Life Sciences and Biotechnology, Korea University, Seoul 02841, Republic of Korea.
authors.forename: Young-Woo
authors.initials: YW
authors.lastname: Sohn
authors.affiliation: Department of Biotechnology, College of Life Sciences and Biotechnology, Korea University, Seoul 02841, Republic of Korea.
authors.forename: Se-Yeong
authors.initials: SY
authors.lastname: Oh
authors.affiliation: Department of Biotechnology, College of Life Sciences and Biotechnology, Korea University, Seoul 02841, Republic of Korea.
authors.forename: Jun-Kyum
authors.initials: JK
authors.lastname: Kim
authors.affiliation: Department of Biotechnology, College of Life Sciences and Biotechnology, Korea University, Seoul 02841, Republic of Korea; Department of Neurosurgery, University of Alabama at Birmingham, Birmingham, AL 35294, USA.
authors.forename: Sung-Hak
authors.initials: SH
authors.lastname: Kim
authors.affiliation: Department of Biotechnology, College of Life Sciences and Biotechnology, Korea University, Seoul 02841, Republic of Korea; Specific Organs Cancer Division, Research Institute and Hospital, National Cancer Center, Goyang 10408, Republic of Korea.
authors.forename: Ji-Eun
authors.initials: JE
authors.lastname: Jung
authors.affiliation: Department of Biotechnology, College of Life Sciences and Biotechnology, Korea University, Seoul 02841, Republic of Korea.
authors.forename: Sungwook
authors.initials: S
authors.lastname: Kwak
authors.affiliation: First Affiliated Hospital of Wenzhou Medical University, Wenzhou 325015, Zhejiang, P.R. China.
authors.forename: Kai-Fu
authors.initials: KF
authors.lastname: Tang
authors.affiliation: First Affiliated Hospital of Wenzhou Medical University, Wenzhou 325015, Zhejiang, P.R. China.
authors.forename: Yunsheng
authors.initials: Y
authors.lastname: Xu
authors.affiliation: Department of Stem Cell Biology and Regenerative Medicine, Lerner Research Institute, Cleveland Clinic, Cleveland, OH 44195, USA.
authors.forename: Jeremy N
authors.initials: JN
authors.lastname: Rich
authors.affiliation: Department of Biotechnology, College of Life Sciences and Biotechnology, Korea University, Seoul 02841, Republic of Korea. Electronic address: hg-kim@korea.ac.kr.
authors.forename: Hyunggee
authors.initials: H
authors.lastname: Kim
mesh_terms: D000818:Animals; D001932:Brain Neoplasms / Q000378:metabolism; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000502:physiology; D044842:Cullin Proteins / Q000378:metabolism*; D005909:Glioblastoma / Q000378:metabolism*; D053823:Hedgehog Proteins / Q000378:metabolism; D006801:Humans; D051798:Inhibitor of Differentiation Protein 1 / Q000378:metabolism*; D051379:Mice; D014411:Neoplastic Stem Cells / Q000378:metabolism*; D060449:Wnt Signaling Pathway / Q000502:physiology*; D051176:beta Catenin / Q000378:metabolism
chemical_list: C503645:CUL3 protein, human; C503646:Cul3 protein, mouse; D044842:Cullin Proteins; D053823:Hedgehog Proteins; C497453:ID1 protein, human; C497455:Idb1 protein, mouse; D051798:Inhibitor of Differentiation Protein 1; C509239:SHH protein, human; C465570:Shh protein, mouse; D051176:beta Catenin
keywords: CULLIN3; DVL2; GLI2; ID1; glioblastoma stem cells