An ID2-dependent mechanism for VHL inactivation in cancer

Mechanisms that maintain cancer stem cells are crucial to tumour progression. The ID2 protein supports cancer hallmarks including the cancer stem cell state. HIF alpha transcription factors, most notably HIF2 alpha (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 HIF2 alpha 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 HIF2 alpha ubiquitylation and degradation. Phosphorylation of Thr27 of ID2 by DYRK1 blocks ID2-VHL interaction and preserves HIF2 alpha ubiquitylation. In glioblastoma, ID2 positively modulates HIF2 alpha activity. Conversely, elevated expression of DYRK1 phosphorylates Thr27 of ID2, leading to HIF2 alpha destabilization, loss of glioma stemness, inhibition of tumour growth, and a more favourable outcome for patients with glioblastoma.