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CIC protein instability contributes to tumorigenesis in glioblastoma

Author

Listed:
  • 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
    UPMC Presbyterian)

  • Stefan Pusch

    (Heidelberg University Hospital
    Clinical Cooperation Unit Neuropathology German Cancer Research Center (DKFZ))

  • 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
    Clinical Cooperation Unit Neuropathology German Cancer Research Center (DKFZ))

  • Gelareh Zadeh

    (Princess Margaret Cancer Centre
    Toronto Western Hospital
    University Health Network and University of Toronto)

  • Kenneth Aldape

    (Princess Margaret Cancer Centre
    National Cancer Institute)

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.

Suggested Citation

  • 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 Alamsa, 2019. "CIC protein instability contributes to tumorigenesis in glioblastoma," Nature Communications, Nature, vol. 10(1), pages 1-17, December.
  • Handle: RePEc:nat:natcom:v:10:y:2019:i:1:d:10.1038_s41467-018-08087-9
    DOI: 10.1038/s41467-018-08087-9
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    Cited by:

    1. Meng Wang & Satoshi Fukushima & Yi-Shuan Sheen & Egle Ramelyte & Noel Cruz-Pacheco & Chenxu Shi & Shanshan Liu & Ishani Banik & Jamie D. Aquino & Martin Sangueza Acosta & Mitchell Levesque & Reinhard , 2024. "The genetic evolution of acral melanoma," Nature Communications, Nature, vol. 15(1), pages 1-13, December.
    2. Sheng-Yan Huang & Sha Gong & Yin Zhao & Ming-Liang Ye & Jun-Yan Li & Qing-Mei He & Han Qiao & Xi-Rong Tan & Jing-Yun Wang & Ye-Lin Liang & Sai-Wei Huang & Shi-Wei He & Ying-Qin Li & Sha Xu & Ying-Qing, 2024. "PJA1-mediated suppression of pyroptosis as a driver of docetaxel resistance in nasopharyngeal carcinoma," Nature Communications, Nature, vol. 15(1), pages 1-17, December.

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