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An ID2-dependent mechanism for VHL inactivation in cancer

Author

Listed:
  • Sang Bae Lee

    (Institute for Cancer Genetics, Columbia University Medical Center)

  • Veronique Frattini

    (Institute for Cancer Genetics, Columbia University Medical Center)

  • Mukesh Bansal

    (Columbia University Medical Center
    Center for Computational Biology and Bioinformatics, Columbia University Medical Center)

  • Angelica M. Castano

    (Institute for Cancer Genetics, Columbia University Medical Center)

  • Dan Sherman

    (NYU School of Medicine)

  • Keino Hutchinson

    (NYU School of Medicine)

  • Jeffrey N. Bruce

    (Columbia University Medical Center)

  • Andrea Califano

    (Columbia University Medical Center
    Center for Computational Biology and Bioinformatics, Columbia University Medical Center)

  • Guangchao Liu

    (Institute for Cancer Genetics, Columbia University Medical Center)

  • Timothy Cardozo

    (NYU School of Medicine)

  • Antonio Iavarone

    (Institute for Cancer Genetics, Columbia University Medical Center
    Columbia University Medical Center
    Columbia University Medical Center)

  • Anna Lasorella

    (Institute for Cancer Genetics, Columbia University Medical Center
    Columbia University Medical Center
    Columbia University Medical Center)

Abstract

Mechanisms that maintain cancer stem cells are crucial to tumour progression. The ID2 protein supports cancer hallmarks including the cancer stem cell state. HIFα transcription factors, most notably HIF2α (also known as EPAS1), are expressed in and required for maintenance of cancer stem cells (CSCs). However, the pathways that are engaged by ID2 or drive HIF2α accumulation in CSCs have remained unclear. Here we report that DYRK1A and DYRK1B kinases phosphorylate ID2 on threonine 27 (Thr27). Hypoxia downregulates this phosphorylation via inactivation of DYRK1A and DYRK1B. The activity of these kinases is stimulated in normoxia by the oxygen-sensing prolyl hydroxylase PHD1 (also known as EGLN2). ID2 binds to the VHL ubiquitin ligase complex, displaces VHL-associated Cullin 2, and impairs HIF2α ubiquitylation and degradation. Phosphorylation of Thr27 of ID2 by DYRK1 blocks ID2–VHL interaction and preserves HIF2α ubiquitylation. In glioblastoma, ID2 positively modulates HIF2α activity. Conversely, elevated expression of DYRK1 phosphorylates Thr27 of ID2, leading to HIF2α destabilization, loss of glioma stemness, inhibition of tumour growth, and a more favourable outcome for patients with glioblastoma.

Suggested Citation

  • Sang Bae Lee & Veronique Frattini & Mukesh Bansal & Angelica M. Castano & Dan Sherman & Keino Hutchinson & Jeffrey N. Bruce & Andrea Califano & Guangchao Liu & Timothy Cardozo & Antonio Iavarone & Ann, 2016. "An ID2-dependent mechanism for VHL inactivation in cancer," Nature, Nature, vol. 529(7585), pages 172-177, January.
    • Handle: RePEc:nat:nature:v:529:y:2016:i:7585:d:10.1038_nature16475
    DOI: 10.1038/nature16475
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    Cited by:

    1. Sang Bae Lee & Luciano Garofano & Aram Ko & Fulvio D’Angelo & Brulinda Frangaj & Danika Sommer & Qiwen Gan & KyeongJin Kim & Timothy Cardozo & Antonio Iavarone & Anna Lasorella, 2022. "Regulated interaction of ID2 with the anaphase-promoting complex links progression through mitosis with reactivation of cell-type-specific transcription," Nature Communications, Nature, vol. 13(1), pages 1-14, December.

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