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 Deimling, Gelareh Zadeh () and Kenneth Aldape ()
Additional contact information
Severa Bunda: Princess Margaret Cancer Centre
Pardeep Heir: Princess Margaret Cancer Centre
Julie Metcalf: Princess Margaret Cancer Centre
Annie Si Cong Li: Princess Margaret Cancer Centre
Sameer Agnihotri: Princess Margaret Cancer Centre
Stefan Pusch: Heidelberg University Hospital
Mamatjan Yasin: Princess Margaret Cancer Centre
Mira Li: Princess Margaret Cancer Centre
Kelly Burrell: Princess Margaret Cancer Centre
Sheila Mansouri: Princess Margaret Cancer Centre
Olivia Singh: Princess Margaret Cancer Centre
Mark Wilson: Princess Margaret Cancer Centre
Amir Alamsahebpour: Princess Margaret Cancer Centre
Romina Nejad: Princess Margaret Cancer Centre
Bethany Choi: Princess Margaret Cancer Centre
David Kim: Princess Margaret Cancer Centre
Andreas Deimling: Heidelberg University Hospital
Gelareh Zadeh: Princess Margaret Cancer Centre
Kenneth Aldape: Princess Margaret Cancer Centre

Nature Communications, 2019, vol. 10, issue 1, 1-17

Abstract: 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.

Date: 2019
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DOI: 10.1038/s41467-018-08087-9

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