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bioRxiv · 10.1101/2020.02.20.957688

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

Schober, A. S.·Martin-Barros, I.·Martin-Mateos, T.·Perez-Andres, E.·Carlevaris, O.·Pozo, S.·Cortazar, A. R.·Aransay, A. M.·Carracedo, A.·Mayor, U.·See, V.·Berra, E.
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Abstract

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 -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- signalling is found in many tumours independently of oxygen availability pointing towards the relevance of non-canonical HIF- regulators. In this study, we establish the Ubiquitin Specific Protease 29 (USP29) as direct post-translational activator of HIF- in a variety of cancer cell lines. USP29 binds to HIF-, decreases poly-ubiquitination and thus protects HIF- from proteasomal degradation. Deubiquitinating activity of USP29 is essential to stabilise not only HIF-1 but also HIF-2, 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.

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Schober, A. S., Martin-Barros, I., Martin-Mateos, T., Perez-Andres, E., Carlevaris, O., Pozo, S., Cortazar, A. R., Aransay, A. M., Carracedo, A., Mayor, U., See, V., Berra, E.. 2020-02-20. USP29 is a novel non-canonical Hypoxia Inducible Factor-α activator. https://doi.org/10.1101/2020.02.20.957688

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