The P-body component USP52/PAN2 is a novel regulator of HIF1A mRNA stability

H1F1A (hypoxia-inducible factor ice) is the master regulator of the cellular response to hypoxia and is implicated in cancer progression. Whereas the regulation of HIF1A protein in response to oxygen is well characterized, less is known about the fate of HIM mRNA. In the present study, we have identified the pseudo-DUB (deubiquitinating enzyme)/deadenylase USP52 (ubiquitin-specific protease 52)/PAN2 [poly(A) nuclease 2] as an important regulator of the HIF1A-mediated hypoxic response. Depletion of USP52 reduced HIF1A mRNA and protein levels and resulted in reduced expression of HIF1A-regulated hypoxic targets due to a 3-UTR (untranslated region)-dependent poly(A)-tail-length-independent destabilization in HIFIA mRNA. MS analysis revealed an association of USP52 with several P-body (processing body) components and we confiuiued further that USP52 protein and HIFIA mRNA co-localized with cytoplasmic P-bodies. Importantly, P-body dispersal by lcnbckdown of GWI82 or LSM1 resulted in a reduction of HIFIA mRNA levels. These data uncover a novel role for P-bodies in regulating HIF1A mRNA stability, and demonstrate that USP52 is a key component of P-bodies required to prevent HIF1A mRNA degradation.