An ID2-dependent mechanism for VHL inactivation in cancer

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 () and Anna Lasorella ()
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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
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
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
Anna Lasorella: Institute for Cancer Genetics, Columbia University Medical Center

Nature, 2016, vol. 529, issue 7585, 172-177

Abstract: 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.

Date: 2016
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DOI: 10.1038/nature16475

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