USP29 is a novel non-canonical Hypoxia Inducible Factor-α activator

Hypoxia Inducible Factor (HIF) is the master transcriptional regulator that orchestrates cellular adaptation to low oxygen. HIF is tightly regulated via the stability of its α-subunit, which is subjected to oxygen-dependent proline hydroxylation by Prolyl-Hydroxylase Domain containing proteins (PHDs/EGLNs), and ultimately targeted for proteasomal degradation through poly-ubiquitination by von-Hippel-Lindau protein (pVHL). However, sustained HIF-α signalling is found in many tumours independently of oxygen availability pointing towards the relevance of non-canonical HIF-α regulators. In this study, we establish the Ubiquitin Specific Protease 29 (USP29) as direct post-translational activator of HIF-α in a variety of cancer cell lines. USP29 binds to HIF-α, decreases poly-ubiquitination and thus protects HIF-α from proteasomal degradation. Deubiquitinating activity of USP29 is essential to stabilise not only HIF-1α but also HIF-2α, via their C-termini in an oxygen/PHD/pVHL-independent manner. Furthermore, in prostate cancer samples the expression of USP29 correlates with the HIF-target gene CA9 (carbonic anhydrase 9) as well as disease progression and severity.