Hypoxia Promotes Cancer Stem Cells via ID2-Dependent VHL Inactivation

The hypoxia-inducible transcription factor α (HIFα) proteins mediate cellular responses to hypoxia, and HIFα signaling is disrupted in cancer by mutations in von-Hippel Lindau (VHL). Both HIF2α and inhibitor of DNA binding 2 (ID2) have been implicated as critical regulators of cancer stem cells (CSC). However, the pathways by which these proteins maintain CSC stemness are not well understood. To investigate potential cross-talk between HIF2α and ID2 in CSCs, Lee and colleagues used mass spectrometry to identify Ser14 and Thr27 as sites of phosphorylation on ID2. Mutation of ID2 Thr27 to an unphosphorylatable Ala residue increased the ability of neural stem cells to form neurospheres. A conserved putative binding motif for the dual specificity tyrosine-(Y)-phosphorylation regulated kinase 1A (DYRK1A) and DYRK1B was found surrounding the Thr27 residue. Consistent with this result, ID2 co-precipitated with DYRK1A/B, and DYRK1 knockdown reduced ID2 phosphorylation at Thr27, indicating that ID2 is phosphorylated by DYRK1. Under normoxia, the activity of DYRK1 kinases was potentiated by prolyl hydroxylase 1, whereas hypoxia reduced Thr27 phosphorylation by preventing DYRK1 autophosphorylation and activity. DYRK1-mediated phosphorylation of ID2 regulated glioma stem cells by reducing the accumulation of HIF2α. ID2 interacted with Elongin C, a component of the VCB–cullin 2 (CUL2) ubiquitin ligase complex, as well as VHL, and DYRK1-mediated phosphorylation of ID2 blocked these interactions. In glioma cells, hypoxia promoted the interaction between VHL and ID2 and disrupted the association with CUL2, allowing for HIF2α stabilization by dissociation from the ubiquitin ligase and preventing ubiquitin-mediated proteasomal degradation. In human glioblastomas, high ID2 activity was associated with increased HIF2α transcriptional activity. Further, deletion of Id1 and Id2 in a mouse model of glioma reduced HIF2α protein expression, and DYRK1B expression in glioma xenografts reduced tumor growth and prolonged survival. Together, these data provide a mechanism by which DYRK1-driven phosphorylation of ID2 leads to HIF2α destabilization, loss of stem cell traits, and tumor reduction.

Lee SB, Frattini V, Bansal M, Castano AM, Sherman D, Hutchinson K, et al. An ID2-dependent mechanism for VHL inactivation in cancer. Nature 2016;529:172–7.

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