Hypoxia Prevents AKT Hydroxylation and Promotes AKT Hyperactivation

VHL is a tumor suppressor commonly inactivated in von Hippel-Lindau (VHL) disease and sporadic clear-cell renal cell carcinomas (ccRCC). Loss of VHL increases sensitivity to mTOR inhibitors, and VHL-defective renal carcinomas are associated with AKT hyperactivation. Thus, Guo and colleagues hypothesized that VHL might directly regulate AKT, and consistent with this hypothesis, deletion of Vhl in mouse embryonic fibroblasts or mutation of VHL in patients with ccRCC increased AKT activity as indicated by increased phosphorylation of threonine 308 (pT308-AKT). Additionally, exposing cells to hypoxic conditions or an inhibitor of the oxygen-dependent hydroxylase EGLN1 reduced AKT phosphorylation in VHL-proficient, but not VHL-deficient, ccRCC cells, indicating that AKT inhibition by VHL is oxygen dependent. AKT bound to EGLN1, and binding of VHL to AKT and subsequent suppression of AKT activity required EGLN1, whereas depletion of EGLN1 increased AKT activity. Mechanistically, EGLN1 hydroxylated AKT at proline residues 125 and 313, and VHL bound to hydroxylated AKT to suppress its activation in an E3 ubiquitin ligase-independent manner through PP2A-mediated dephosphorylation of pT308-AKT. Hydroxylation-deficient AKT mutants induced enhanced anchorage-independent growth in vitro and tumor formation in vivo compared with wild-type AKT, demonstrating that hydroxylation of AKT modulates oncogenic signaling. Moreover, two cancer-associated mutations, AKT1^G311D and AKT2^P127N, were identified that reduce AKT hydroxylation, disrupt the VHL–AKT interaction, and enhance AKT activation. Taken together, these results indicate that hypoxia and defects in the VHL–EGLN pathway lead to hydroxylation-dependent hyperactivation of AKT, and suggest that targeting the AKT pathway may be effective in patients with VHL-deficient tumors as well as more generally in hypoxic tumors.

Guo J, Chakraborty AA, Liu P, Gan W, Zheng X, Inuzuka H, et al. pVHL suppresses kinase activity of Akt in a proline-hydroxylation–dependent manner. Science 2016;353:929–32.

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