Colorectal cancer ranks among the third most common human malignant diseases and is one of the leading causes of cancer-related deaths globally. Colon cancer cells are hypoxic and display disturbed protein homeostasis. Ubiquitin-ligase-initiated proteasomal degradation as well as its prevention by deubiquitinases (DUBs) are supposed to contribute to the above-mentioned disturbances. However, not much is known about the involvement of ubiquitinating and deubiquitinating enzymes in colon cancer and their effect on the hypoxia response. Here, we identify the DUB ubiquitin-specific protease 10 (USP10) as an important player in the control of colon cancer progression and a new modifier of the hypoxia response. Mechanistically, we show that knockout of USP10 in different colon cancer cells causes an elevation in HIF-1α but not HIF-2α protein levels under both normoxic and hypoxic conditions. In addition, the lack of USP10 increased cellular migration, reduced cell adhesion, and switched the energy phenotype towards increased glycolysis and enhanced extracellular acidification. These changes were at least partially caused by HIF-1α, as the knockdown of HIF-1α rescued the cellular phenotype caused by USP10 deficiency. Interestingly, the USP10-dependent increase in HIF-1 α was neither caused by enhanced transcription nor prolonged half-life but via mTOR/S6K mediated HIF-1α protein synthesis. Together, the current findings indicate that USP10 is able to participate in colon carcinogenesis by modulating the hypoxia response and may therefore represent a new therapeutic target.