Role of yUbp8 in Mitochondria and Hypoxia Entangles the 2 Finding of Human Ortholog Usp22 in the Glioblastoma 3 Pseudo-Palisade Microlayer

K-Acetyltransferase (KAT) Gcn5 and ubiquitin protease (DUB) Ubp8 are required for res- 13 piration and mitochondria functions in budding yeast, and, in this study, we show that loss of res- 14 piratory activity is acquired in time. Interestingly, we show that the absence of Ubp8 allows cells to 15 grow in hypoxic conditions with altered mitophagy. Comparatively, the aggressive glioblastoma 16 (GBM) multiforme tumor shows survival mechanisms to overcome hypoxia in the brain. Starting 17 from yeast and our findings on the role of Ubp8 in hypoxia, we extended our analysis to the human 18 ortholog and signature cancer gene Usp22 in glioblastoma tumor specimens. Here we demonstrate 19 that Usp22 is localized and overexpressed in the pseudo-palisade tissue around the necrosis area of 20 the tumor. In addition, Usp22 colocalizes with the mitophagy marker Parkin indicating a link with 21 mitochondria functions in GBM. Collectively, this evidence suggests that altered expression of 22 Usp22 might provide a way for tumor cells to survive in hypoxic conditions, allowing the escape of 23 cells from the necrosis area toward vascularized tissues. Collectively our experimental data suggest 24 a model for a possible way of uncontrolled proliferation and invasion of glioblastoma.