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

doi:10.1016/j.celrep.2016.06.092

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 journal › Article › peer-review

39 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 language	English
Pages (from-to)	1629-1641
Number of pages	13
Journal	Cell Reports
Volume	16
Issue number	6
DOIs	https://doi.org/10.1016/j.celrep.2016.06.092
Publication status	Published - 2016 Aug 9

Keywords

CULLIN3
DVL2
GLI2
ID1
glioblastoma stem cells

ASJC Scopus subject areas

Biochemistry, Genetics and Molecular Biology(all)

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10.1016/j.celrep.2016.06.092

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@article{b074dd3766d84def99d432ff52476d58,

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.",

keywords = "CULLIN3, DVL2, GLI2, ID1, glioblastoma stem cells",

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

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: {\textcopyright} 2016 The Author(s)",

year = "2016",

month = aug,

day = "9",

doi = "10.1016/j.celrep.2016.06.092",

language = "English",

volume = "16",

pages = "1629--1641",

journal = "Cell Reports",

issn = "2211-1247",

publisher = "Cell Press",

number = "6",

}

TY - JOUR

T1 - The ID1-CULLIN3 Axis Regulates Intracellular SHH and WNT Signaling in Glioblastoma Stem Cells

AU - Jin, Xun

AU - Jeon, Hye Min

AU - Jin, Xiong

AU - Kim, Eun Jung

AU - Yin, Jinlong

AU - Jeon, Hee Young

AU - Sohn, Young Woo

AU - Oh, Se Yeong

AU - Kim, Jun Kyum

AU - Kim, Sung Hak

AU - Jung, Ji Eun

AU - Kwak, Sungwook

AU - Tang, Kai Fu

AU - Xu, Yunsheng

AU - Rich, Jeremy N.

AU - Kim, Hyunggee

N1 - 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)

PY - 2016/8/9

Y1 - 2016/8/9

N2 - 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.

AB - 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.

KW - CULLIN3

KW - DVL2

KW - GLI2

KW - ID1

KW - glioblastoma stem cells

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U2 - 10.1016/j.celrep.2016.06.092

DO - 10.1016/j.celrep.2016.06.092

M3 - Article

C2 - 27477274

AN - SCOPUS:84979743444

SN - 2211-1247

VL - 16

SP - 1629

EP - 1641

JO - Cell Reports

JF - Cell Reports

IS - 6

ER -

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

Abstract

Keywords

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