CIC protein instability contributes to tumorigenesis in glioblastoma

Severa Bunda; Pardeep Heir; Julie Metcalf; Annie Si Cong Li; Sameer Agnihotri; Stefan Pusch; Mamatjan Yasin; Mira Li; Kelly Burrell; Sheila Mansouri; Olivia Singh; Mark Wilson; Amir Alamsahebpour; Romina Nejad; Bethany Choi; David Kim; Andreas von Deimling; Gelareh Zadeh; Kenneth Aldape

doi:10.1038/s41467-018-08087-9

CIC protein instability contributes to tumorigenesis in glioblastoma

Severa Bunda, Pardeep Heir, Julie Metcalf, Annie Si Cong Li, Sameer Agnihotri, Stefan Pusch, Mamatjan Yasin, Mira Li, Kelly Burrell, Sheila Mansouri, Olivia Singh, Mark Wilson, Amir Alamsahebpour, Romina Nejad, Bethany Choi, David Kim, Andreas von Deimling, Gelareh Zadeh, Kenneth Aldape

Research output: Contribution to journal › Article › peer-review

53 Scopus citations

Abstract

Capicua (CIC) is a transcriptional repressor that counteracts activation of genes downstream of receptor tyrosine kinase (RTK)/Ras/ERK signaling. It is well-established that tumorigenesis, especially in glioblastoma (GBM), is attributed to hyperactive RTK/Ras/ERK signaling. While CIC is mutated in other tumors, here we show that CIC has a tumor suppressive function in GBM through an alternative mechanism. We find that CIC protein levels are negligible in GBM due to continuous proteasome-mediated degradation, which is mediated by the E3 ligase PJA1 and show that this occurs through binding of CIC to its DNA target and phosphorylation on residue S173. PJA1 knockdown increased CIC stability and extended survival using in-vivo models of GBM. Deletion of the ERK binding site resulted in stabilization of CIC and increased therapeutic efficacy of ERK inhibition in GBM models. Our results provide a rationale to target CIC degradation in Ras/ERK-driven tumors, including GBM, to increase efficacy of ERK inhibitors.

Original language	English (US)
Article number	661
Journal	Nature communications
Volume	10
Issue number	1
DOIs	https://doi.org/10.1038/s41467-018-08087-9
State	Published - Dec 1 2019
Externally published	Yes

ASJC Scopus subject areas

General Chemistry
General Biochemistry, Genetics and Molecular Biology
General Physics and Astronomy

Access to Document

10.1038/s41467-018-08087-9

Cite this

Bunda, S., Heir, P., Metcalf, J., Li, A. S. C., Agnihotri, S., Pusch, S., Yasin, M., Li, M., Burrell, K., Mansouri, S., Singh, O., Wilson, M., Alamsahebpour, A., Nejad, R., Choi, B., Kim, D., von Deimling, A., Zadeh, G., & Aldape, K. (2019). CIC protein instability contributes to tumorigenesis in glioblastoma. Nature communications, 10(1), Article 661. https://doi.org/10.1038/s41467-018-08087-9

Bunda, S, Heir, P, Metcalf, J, Li, ASC, Agnihotri, S, Pusch, S, Yasin, M, Li, M, Burrell, K, Mansouri, S, Singh, O, Wilson, M, Alamsahebpour, A, Nejad, R, Choi, B, Kim, D, von Deimling, A, Zadeh, G & Aldape, K 2019, 'CIC protein instability contributes to tumorigenesis in glioblastoma', Nature communications, vol. 10, no. 1, 661. https://doi.org/10.1038/s41467-018-08087-9

@article{d72ecae5694a4e8585bcc1981c8905b8,

title = "CIC protein instability contributes to tumorigenesis in glioblastoma",

abstract = "Capicua (CIC) is a transcriptional repressor that counteracts activation of genes downstream of receptor tyrosine kinase (RTK)/Ras/ERK signaling. It is well-established that tumorigenesis, especially in glioblastoma (GBM), is attributed to hyperactive RTK/Ras/ERK signaling. While CIC is mutated in other tumors, here we show that CIC has a tumor suppressive function in GBM through an alternative mechanism. We find that CIC protein levels are negligible in GBM due to continuous proteasome-mediated degradation, which is mediated by the E3 ligase PJA1 and show that this occurs through binding of CIC to its DNA target and phosphorylation on residue S173. PJA1 knockdown increased CIC stability and extended survival using in-vivo models of GBM. Deletion of the ERK binding site resulted in stabilization of CIC and increased therapeutic efficacy of ERK inhibition in GBM models. Our results provide a rationale to target CIC degradation in Ras/ERK-driven tumors, including GBM, to increase efficacy of ERK inhibitors.",

author = "Severa Bunda and Pardeep Heir and Julie Metcalf and Li, {Annie Si Cong} and Sameer Agnihotri and Stefan Pusch and Mamatjan Yasin and Mira Li and Kelly Burrell and Sheila Mansouri and Olivia Singh and Mark Wilson and Amir Alamsahebpour and Romina Nejad and Bethany Choi and David Kim and {von Deimling}, Andreas and Gelareh Zadeh and Kenneth Aldape",

note = "Publisher Copyright: {\textcopyright} 2019, The Author(s).",

year = "2019",

month = dec,

day = "1",

doi = "10.1038/s41467-018-08087-9",

language = "English (US)",

volume = "10",

journal = "Nature communications",

issn = "2041-1723",

publisher = "Nature Publishing Group",

number = "1",

}

TY - JOUR

T1 - CIC protein instability contributes to tumorigenesis in glioblastoma

AU - Bunda, Severa

AU - Heir, Pardeep

AU - Metcalf, Julie

AU - Li, Annie Si Cong

AU - Agnihotri, Sameer

AU - Pusch, Stefan

AU - Yasin, Mamatjan

AU - Li, Mira

AU - Burrell, Kelly

AU - Mansouri, Sheila

AU - Singh, Olivia

AU - Wilson, Mark

AU - Alamsahebpour, Amir

AU - Nejad, Romina

AU - Choi, Bethany

AU - Kim, David

AU - von Deimling, Andreas

AU - Zadeh, Gelareh

AU - Aldape, Kenneth

PY - 2019/12/1

Y1 - 2019/12/1

N2 - Capicua (CIC) is a transcriptional repressor that counteracts activation of genes downstream of receptor tyrosine kinase (RTK)/Ras/ERK signaling. It is well-established that tumorigenesis, especially in glioblastoma (GBM), is attributed to hyperactive RTK/Ras/ERK signaling. While CIC is mutated in other tumors, here we show that CIC has a tumor suppressive function in GBM through an alternative mechanism. We find that CIC protein levels are negligible in GBM due to continuous proteasome-mediated degradation, which is mediated by the E3 ligase PJA1 and show that this occurs through binding of CIC to its DNA target and phosphorylation on residue S173. PJA1 knockdown increased CIC stability and extended survival using in-vivo models of GBM. Deletion of the ERK binding site resulted in stabilization of CIC and increased therapeutic efficacy of ERK inhibition in GBM models. Our results provide a rationale to target CIC degradation in Ras/ERK-driven tumors, including GBM, to increase efficacy of ERK inhibitors.

AB - Capicua (CIC) is a transcriptional repressor that counteracts activation of genes downstream of receptor tyrosine kinase (RTK)/Ras/ERK signaling. It is well-established that tumorigenesis, especially in glioblastoma (GBM), is attributed to hyperactive RTK/Ras/ERK signaling. While CIC is mutated in other tumors, here we show that CIC has a tumor suppressive function in GBM through an alternative mechanism. We find that CIC protein levels are negligible in GBM due to continuous proteasome-mediated degradation, which is mediated by the E3 ligase PJA1 and show that this occurs through binding of CIC to its DNA target and phosphorylation on residue S173. PJA1 knockdown increased CIC stability and extended survival using in-vivo models of GBM. Deletion of the ERK binding site resulted in stabilization of CIC and increased therapeutic efficacy of ERK inhibition in GBM models. Our results provide a rationale to target CIC degradation in Ras/ERK-driven tumors, including GBM, to increase efficacy of ERK inhibitors.

UR - http://www.scopus.com/inward/record.url?scp=85061271680&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=85061271680&partnerID=8YFLogxK

U2 - 10.1038/s41467-018-08087-9

DO - 10.1038/s41467-018-08087-9

M3 - Article

C2 - 30737375

AN - SCOPUS:85061271680

SN - 2041-1723

VL - 10

JO - Nature communications

JF - Nature communications

IS - 1

M1 - 661

ER -

CIC protein instability contributes to tumorigenesis in glioblastoma

Abstract

ASJC Scopus subject areas

Access to Document

Other files and links

Fingerprint

Cite this