European contribution to the study of ROS: A summary of the findings and prospects for the future from the COST action BM1203 (EU-ROS).

The European Cooperation in Science and Technology (COST) provides an ideal framework to establish multi-disciplinary research networks. COST Action BM1203 (EU-ROS) represents a consortium of researchers from different disciplines who are dedicated to providing new insights and tools for better understanding redox biology and medicine and, in the long run, to finding new therapeutic strategies to target dysregulated redox processes in various diseases. This report highlights the major achievements of EU-ROS as well as research updates and new perspectives arising from its members. The EU-ROS consortium comprised more than 140 active members who worked together for four years on the topics briefly described below. The formation of reactive oxygen and nitrogen species (RONS) is an established hallmark of our aerobic environment and metabolism but RONS also act as messengers via redox regulation of essential cellular processes. The fact that many diseases have been found to be associated with oxidative stress established the theory of oxidative stress as a trigger of diseases that can be corrected by antioxidant therapy. However, while experimental studies support this thesis, clinical studies still generate controversial results, due to complex pathophysiology of oxidative stress in humans. For future improvement of antioxidant therapy and better understanding of redox-associated disease progression detailed knowledge on the sources and targets of RONS formation and discrimination of their detrimental or beneficial roles is required. In order to advance this important area of biology and medicine, highly synergistic approaches combining a variety of diverse and contrasting disciplines are needed.The EU-ROS consortium (COST Action BM1203) was supported by the European Cooperation in Science and Technology (COST). The present overview represents the final Action dissemination summarizing the major achievements of COST Action BM1203 (EU-ROS) as well as research news and personal views of its members. Some authors were also supported by COST Actions BM1005 (ENOG) and BM1307 (PROTEOSTASIS), as well as funding from the European Commission FP7 and H2020 programmes, and several national funding agencies

USP10 Contributes to Colon Carcinogenesis via mTOR/S6K Mediated HIF-1α but Not HIF-2α Protein Synthesis

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

Involvement of E3 ligases and deubiquitinases in the control of HIF-α subunit abundance

Abstract The ubiquitin and hypoxia-inducible factor (HIF) pathways are cellular processes involved in the regulation of a variety of cellular functions. Enzymes called ubiquitin E3 ligases perform protein ubiquitylation. The action of these enzymes can be counteracted by another group of enzymes called deubiquitinases (DUBs), which remove ubiquitin from target proteins. The balanced action of these enzymes allows cells to adapt their protein content to a variety of cellular and environmental stress factors, including hypoxia. While hypoxia appears to be a powerful regulator of the ubiquitylation process, much less is known about the impact of DUBs on the HIF system and hypoxia-regulated DUBs. Moreover, hypoxia and DUBs play crucial roles in many diseases, such as cancer. Hence, DUBs are considered to be promising targets for cancer cell-specific treatment. Here, we review the current knowledge about the role DUBs play in the control of HIFs, the regulation of DUBs by hypoxia, and their implication in cancer progression

USP10 contributes to colon carcinogenesis via mTOR/S6K mediated HIF-1α but not HIF-2α protein synthesis

Abstract 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

DUBs, hypoxia, and cancer

Abstract Alterations in protein ubiquitylation and hypoxia are commonly associated with cancer. Ubiquitylation is carried out by three sequentially acting ubiquitylating enzymes and can be opposed by deubiquitinases (DUBs), which have emerged as promising drug targets. Apart from protein localization and activity, ubiquitylation regulates degradation of proteins, among them hypoxia-inducible factors (HIFs). Thereby, various E3 ubiquitin ligases and DUBs regulate HIF abundance. Conversely, several E3s and DUBs are regulated by hypoxia. While hypoxia is a powerful HIF regulator, less is known about hypoxia-regulated DUBs and their impact on HIFs. Here, we review current knowledge about the relationship of E3s, DUBs, and hypoxia signaling. We also discuss the reciprocal regulation of DUBs by hypoxia and use of DUB-specific drugs in cancer

Mitochondrial dysfunction due to lack of manganese superoxide dismutase promotes hepatocarcinogenesis

Abstract Aims: One of the cancer hallmarks is mitochondrial dysfunction associated with oxidative stress. Among the first line of defense against oxidative stress is the dismutation of superoxide radicals, which in the mitochondria is carried out by manganese superoxide dismutase (MnSOD). Accordingly, carcinogenesis would be associated with a dysregulation in MnSOD expression. However, the association studies available so far are conflicting, and no direct proof concerning the role of MnSOD as a tumor promoter or suppressor has been provided. Therefore, we investigated the role of MnSOD in carcinogenesis by studying the effect of MnSOD deficiency in cells and in the livers of mice. Results: We found that loss of MnSOD in hepatoma cells contributed to their conversion toward a more malignant phenotype, affecting all cellular properties generally associated with metabolic transformation and tumorigenesis. In vivo, hepatocyte-specific MnSOD-deficient mice showed changed organ architecture, increased expression of tumor markers, and a faster response to carcinogenesis. Moreover, deficiency of MnSOD in both the in vitro and in vivo model reduced β-catenin and hypoxia-inducible factor-1⍺ levels. Innovation: The present study shows for the first time the important correlation between MnSOD presence and the regulation of two major pathways involved in carcinogenesis, the Wnt/β-catenin and hypoxia signaling pathway. Conclusion: Our study points toward a tumor suppressive role of MnSOD in liver, where the Wnt/β-catenin and hypoxia pathway may be crucial elements

ER-stress promotes VHL-independent degradation of hypoxia-inducible factors via FBXW1A/βTrCP

Abstract Metabolic adaptation and signal integration in response to hypoxic conditions is mainly regulated by hypoxia-inducible factors (HIFs). At the same time, hypoxia induces ROS formation and activates the unfolded protein response (UPR), indicative of endoplasmic reticulum (ER) stress. However, whether ER stress would affect the hypoxia response remains ill-defined. Here we report that feeding mice a high fat diet causes ER stress and attenuates the response to hypoxia. Mechanistically, ER stress promotes HIF-1α and HIF-2α degradation independent of ROS, Ca²⁺, and the von Hippel-Lindau (VHL) pathway, involving GSK3β and the ubiquitin ligase FBXW1A/βTrCP. Thereby, we reveal a previously unknown function of the GSK3β/HIFα/βTrCP1 axis in ER homeostasis and demonstrate that inhibition of the HIF-1 and HIF-2 response and genetic deficiency of GSK3β affects proliferation, migration, and sensitizes cells for ER stress promoted apoptosis. Vice versa, we show that hypoxia affects the ER stress response mainly through the PERK-arm of the UPR. Overall, we discovered previously unrecognized links between the HIF pathway and the ER stress response and uncovered an essential survival pathway for cells under ER stress

European contribution to the study of ROS: A summary of the findings and prospects for the future from the COST action BM1203 (EU-ROS)

The European Cooperation in Science and Technology (COST) provides an ideal framework to establish multi-disciplinary research networks. COST Action BM1203 (EU-ROS) represents a consortium of researchers from different disciplines who are dedicated to providing new insights and tools for better understanding redox biology and medicine and, in the long run, to finding new therapeutic strategies to target dysregulated redox processes in various diseases. This report highlights the major achievements of EU-ROS as well as research updates and new perspectives arising from its members. The EU-ROS consortium comprised more than 140 active members who worked together for four years on the topics briefly described below. The formation of reactive oxygen and nitrogen species (RONS) is an established hallmark of our aerobic environment and metabolism but RONS also act as messengers via redox regulation of essential cellular processes. The fact that many diseases have been found to be associated with oxidative stress established the theory of oxidative stress as a trigger of diseases that can be corrected by antioxidant therapy. However, while experimental studies support this thesis, clinical studies still generate controversial results, due to complex pathophysiology of oxidative stress in humans. For future improvement of antioxidant therapy and better understanding of redox-associated disease progression detailed knowledge on the sources and targets of RONS formation and discrimination of their detrimental or beneficial roles is required. In order to advance this important area of biology and medicine, highly synergistic approaches combining a variety of diverse and contrasting disciplines are needed

European contribution to the study of ROS: A summary of the findings and prospects for the future from the COST action BM1203 (EU-ROS)

The European Cooperation in Science and Technology (COST) provides an ideal framework to establish multi-disciplinary research networks. COST Action BM1203 (EU-ROS) represents a consortium of researchers from different disciplines who are dedicated to providing new insights and tools for better understanding redox biology and medicine and, in the long run, to finding new therapeutic strategies to target dysregulated redox processes in various diseases. This report highlights the major achievements of EU-ROS as well as research updates and new perspectives arising from its members. The EU-ROS consortium comprised more than 140 active members who worked together for four years on the topics briefly described below. The formation of reactive oxygen and nitrogen species (RONS) is an established hallmark of our aerobic environment and metabolism but RONS also act as messengers via redox regulation of essential cellular processes. The fact that many diseases have been found to be associated with oxidative stress established the theory of oxidative stress as a trigger of diseases that can be corrected by antioxidant therapy. However, while experimental studies support this thesis, clinical studies still generate controversial results, due to complex pathophysiology of oxidative stress in humans. For future improvement of antioxidant therapy and better understanding of redox-associated disease progression detailed knowledge on the sources and targets of RONS formation and discrimination of their detrimental or beneficial roles is required. In order to advance this important area of biology and medicine, highly synergistic approaches combining a variety of diverse and contrasting disciplines are needed