Ferroptosis Regulator Information

General Information of the Ferroptosis Regulator (ID: REG10302)
Regulator Name Ubiquitin thioesterase OTUB1 (OTUB1)
Synonyms
OTB1, OTU1; Deubiquitinating enzyme OTUB1; OTU domain-containing ubiquitin aldehyde-binding protein 1; Otubain-1; Ubiquitin-specific-processing protease OTUB1
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Gene Name OTUB1
Gene ID 55611
Regulator Type Protein coding
Uniprot ID Q96FW1
Sequence
MAAEEPQQQKQEPLGSDSEGVNCLAYDEAIMAQQDRIQQEIAVQNPLVSERLELSVLYKE
YAEDDNIYQQKIKDLHKKYSYIRKTRPDGNCFYRAFGFSHLEALLDDSKELQRFKAVSAK
SKEDLVSQGFTEFTIEDFHNTFMDLIEQVEKQTSVADLLASFNDQSTSDYLVVYLRLLTS
GYLQRESKFFEHFIEGGRTVKEFCQQEVEPMCKESDHIHIIALAQALSVSIQVEYMDRGE
GGTTNPHIFPEGSEPKVYLLYRPGHYDILYK

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Family Peptidase C65 family
Function
Hydrolase that can specifically remove 'Lys-48'-linked conjugated ubiquitin from proteins and plays an important regulatory role at the level of protein turnover by preventing degradation. Regulator of T-cell anergy, a phenomenon that occurs when T-cells are rendered unresponsive to antigen rechallenge and no longer respond to their cognate antigen. Acts via its interaction with RNF128/GRAIL, a crucial inductor of CD4 T-cell anergy. Isoform 1 destabilizes RNF128, leading to prevent anergy. In contrast, isoform 2 stabilizes RNF128 and promotes anergy. Surprisingly, it regulates RNF128-mediated ubiquitination, but does not deubiquitinate polyubiquitinated RNF128. Deubiquitinates estrogen receptor alpha (ESR1). Mediates deubiquitination of 'Lys-48'-linked polyubiquitin chains, but not 'Lys- 63'-linked polyubiquitin chains. Not able to cleave di-ubiquitin. Also capable of removing NEDD8 from NEDD8 conjugates, but with a much lower preference compared to 'Lys-48'-linked ubiquitin.; Plays a key non-catalytic role in DNA repair regulation by inhibiting activity of RNF168, an E3 ubiquitin-protein ligase that promotes accumulation of 'Lys-63'-linked histone H2A and H2AX at DNA damage sites. Inhibits RNF168 independently of ubiquitin thioesterase activity by binding and inhibiting UBE2N/UBC13, the E2 partner of RNF168, thereby limiting spreading of 'Lys-63'-linked histone H2A and H2AX marks. Inhibition occurs by binding to free ubiquitin: free ubiquitin acts as an allosteric regulator that increases affinity for UBE2N/UBC13 and disrupts interaction with UBE2V1. The OTUB1- UBE2N/UBC13-free ubiquitin complex adopts a configuration that mimics a cleaved 'Lys48'-linked di-ubiquitin chain.

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HGNC ID
HGNC:23077
KEGG ID hsa:55611
Full List of the Ferroptosis Target of This Regulator and Corresponding Disease/Drug Response(s)
OTUB1 can regulate the following target(s), and cause disease/drug response(s). You can browse detail information of target(s) or disease/drug response(s).
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Cystine/glutamate transporter (SLC7A11) [Driver; Suppressor]
 Target Info 
In total 4 item(s) under this target
Experiment 1 Reporting the Ferroptosis Target of This Regulator [1]
Target for Ferroptosis Suppressor
Responsed Disease Pancreatic cancer ICD-11: 2C10
 Disease Info 
Responsed Drug Solasonine Investigative
 Drug Info 
Pathway Response Fatty acid metabolism hsa01212
Ferroptosis hsa04216
Apoptosis hsa04210
Ubiquitin mediated proteolysis hsa04120
Cell Process Cell ferroptosis
Cell apoptosis
Cell proliferation
Cell migration
Cell invasion
In Vitro Model
 PANC-1 cells Pancreatic ductal adenocarcinoma Homo sapiens CVCL_0480
CFPAC-1 cells Pancreatic ductal adenocarcinoma Homo sapiens CVCL_1119
In Vivo Model
For xenograft assays, we subcutaneously injected 1 x 106 PANC-1 and CFPAC-1 into the right side of each male nude mouse (n = 6). Tumor volumes (length x width2 x 0.5) were measured at specified time points. For one treatment cycle in a week (starting from week 1 to week 5), solasonine (40 or 80 mg/kg, oral administration, 2 times) were given. A total of five treatment cycles were conducted in this experiment.

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Response regulation Solasonine is involved in ferroptosis by suppressing TFAP2A-mediated transcriptional upregulation of OTUB1, thereby activating ubiquitinated degradation of SLC7A11 and promoting pancreatic cancer cell ferroptosis.
Experiment 2 Reporting the Ferroptosis Target of This Regulator [2]
Target for Ferroptosis Suppressor
Responsed Disease Breast cancer ICD-11: 2C60
 Disease Info 
Pathway Response Fatty acid metabolism hsa01212
Ubiquitin mediated proteolysis hsa04120
Cell Process Cell ferroptosis
In Vitro Model
 BT-474 cells Invasive breast carcinoma Homo sapiens CVCL_0179
SK-BR-3 cells Breast adenocarcinoma Homo sapiens CVCL_0033
In Vivo Model
A total of 24 NOD/SCID mice were purchased from Model Animal Research Center and grown under specific-pathogen-free condition. Mice were randomly divided into three groups (n = 8 per group), BT474-Tr cells were inoculated orthotopically onto the abdominal mammary fat pad. After 1 week, mice were treated with erastin (15 mg/kg intraperitoneal, twice every other day). Erastin was dissolved in 5% DMSO + corn oil (C8267, Sigma). To better dissolve erastin, we warmed the tube at 37 water bath and shook it gently. At the end of the sixth week, all mice were sacrificed, tumor tissues were collected and weighed.

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Response regulation Knockdown of circ-BGN inhibited breast cancer cell viability and notably restored its sensitivity to trastuzumab. Further, we found that circ-BGN could directly bind to OTUB1 and SLC7A11, enhancing OTUB1-mediated SLC7A11 deubiquitination and thereby inhibiting ferroptosis.
Experiment 3 Reporting the Ferroptosis Target of This Regulator [3]
Target for Ferroptosis Suppressor
Responsed Disease Injury of intra-abdominal organs ICD-11: NB91
 Disease Info 
Pathway Response Fatty acid metabolism hsa01212
Ferroptosis hsa04216
Ubiquitin mediated proteolysis hsa04120
Cell Process Cell ferroptosis
In Vitro Model
 mPHs (Mouse primary hepatocytes)
In Vivo Model
ALI induction was performed in 6-8-week-old age-matched C57BL/6J male mice (n = 10-12 per group) by intraperitoneal injection of 3 mL/kg CCl4 in coconut oil. Control and negative control mice were injected with PBS and coconut oil, respectively. At 6 h after injection of CCl4, mice were divided into three groups: CCl4 group, injected with 100 uL PBS (supplemented with 2% mouse serum) through a tail vein; CCl4 + MSC group, injected with 5 x 105 MSCs suspended in 100 uL PBS (supplemented with 2% mouse serum) through a tail vein; CCl4 + Fer-1 group, intraperitoneally injected with ferrostatin-1 (Fer-1, a ferroptosis inhibitor, 2.5 umol/kg body weight). Erastin, intraperitoneal injection of erastin (a ferroptosis inducer, 30 mg/kg body weight) twice every other day, and then the mice were divided into two groups (n = 10-12 per group): Erastin group, injected with 100 uL PBS (supplemented with 2% mouse serum) through a tail vein; Erastin + MSC group, injected with 5 x 105 MSCs suspended in 100 uL PBS (supplemented with 2% mouse serum) through the tail vein.

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Response regulation MSC-Exo protected against CCl4-induced acute liver injury (ALI) through inhibiting hepatocyte ferroptosis via restoring the SLC7A11 protein level. Additionally, the exosome-induced recovery of SLC7A11 protein was accompanied by upregulations of CD44 and OTUB1.
Experiment 4 Reporting the Ferroptosis Target of This Regulator [4]
Target for Ferroptosis Suppressor
Responsed Disease Health ICD-11: N.A.
 Disease Info 
Pathway Response Fatty acid metabolism hsa01212
Ubiquitin mediated proteolysis hsa04120
Cell Process Cell ferroptosis
In Vitro Model
 HEK293 cells Normal Homo sapiens CVCL_0045
SK-N-BE(2)-C cells Neuroblastoma Homo sapiens CVCL_0529
U2OS cells Osteosarcoma Homo sapiens CVCL_0042
HCT 116 cells Colon carcinoma Homo sapiens CVCL_0291
SK-RC-42 cells Renal cell carcinoma Homo sapiens CVCL_6192
NCI-H1299 cells Lung large cell carcinoma Homo sapiens CVCL_0060
T24 cells Bladder carcinoma Homo sapiens CVCL_0554
UM-UC-3 cells Bladder carcinoma Homo sapiens CVCL_1783
SW780 cells Bladder carcinoma Homo sapiens CVCL_1728
In Vivo Model
5.0 x 106 cells were mixed with Matrigel (BD Biosciences) at 1:1 ratio (v/v) and injected subcutaneously into seven-week old nude mice (NU/NU; Charles River). Mice were fed with regular chow. After nine weeks, the mice were killed and the tumors were weighed and recorded.

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Response regulation Overexpression of the cancer stem cell marker CD44 enhanced the stability of SLC7A11 by promoting the interaction between SLC7A11 and OTUB1; depletion of CD44 partially abrogated this interaction. CD44 expression suppressed ferroptosis in cancer cells in an OTUB1-dependent manner.
Pancreatic cancer [ICD-11: 2C10]
 Disease Info 
In total 1 item(s) under this disease
Experiment 1 Reporting the Ferroptosis-centered Disease Response [1]
Target Regulator Ubiquitin thioesterase OTUB1 (OTUB1) Protein coding
 Regulator Info 
Responsed Drug Solasonine Investigative
 Drug Info 
Pathway Response Fatty acid metabolism hsa01212
Ferroptosis hsa04216
Apoptosis hsa04210
Ubiquitin mediated proteolysis hsa04120
Cell Process Cell ferroptosis
Cell apoptosis
Cell proliferation
Cell migration
Cell invasion
In Vitro Model
 PANC-1 cells Pancreatic ductal adenocarcinoma Homo sapiens CVCL_0480
CFPAC-1 cells Pancreatic ductal adenocarcinoma Homo sapiens CVCL_1119
In Vivo Model
For xenograft assays, we subcutaneously injected 1 x 106 PANC-1 and CFPAC-1 into the right side of each male nude mouse (n = 6). Tumor volumes (length x width2 x 0.5) were measured at specified time points. For one treatment cycle in a week (starting from week 1 to week 5), solasonine (40 or 80 mg/kg, oral administration, 2 times) were given. A total of five treatment cycles were conducted in this experiment.

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Response regulation Solasonine is involved in ferroptosis by suppressing TFAP2A-mediated transcriptional upregulation of OTUB1, thereby activating ubiquitinated degradation of SLC7A11 and promoting pancreatic cancer cell ferroptosis.
Breast cancer [ICD-11: 2C60]
 Disease Info 
In total 1 item(s) under this disease
Experiment 1 Reporting the Ferroptosis-centered Disease Response [2]
Target Regulator Ubiquitin thioesterase OTUB1 (OTUB1) Protein coding
 Regulator Info 
Pathway Response Fatty acid metabolism hsa01212
Ubiquitin mediated proteolysis hsa04120
Cell Process Cell ferroptosis
In Vitro Model
 BT-474 cells Invasive breast carcinoma Homo sapiens CVCL_0179
SK-BR-3 cells Breast adenocarcinoma Homo sapiens CVCL_0033
In Vivo Model
A total of 24 NOD/SCID mice were purchased from Model Animal Research Center and grown under specific-pathogen-free condition. Mice were randomly divided into three groups (n = 8 per group), BT474-Tr cells were inoculated orthotopically onto the abdominal mammary fat pad. After 1 week, mice were treated with erastin (15 mg/kg intraperitoneal, twice every other day). Erastin was dissolved in 5% DMSO + corn oil (C8267, Sigma). To better dissolve erastin, we warmed the tube at 37 water bath and shook it gently. At the end of the sixth week, all mice were sacrificed, tumor tissues were collected and weighed.

    Click to Show/Hide
Response regulation Knockdown of circ-BGN inhibited breast cancer cell viability and notably restored its sensitivity to trastuzumab. Further, we found that circ-BGN could directly bind to OTUB1 and SLC7A11, enhancing OTUB1-mediated SLC7A11 deubiquitination and thereby inhibiting ferroptosis.
Injury of intra-abdominal organs [ICD-11: NB91]
 Disease Info 
In total 1 item(s) under this disease
Experiment 1 Reporting the Ferroptosis-centered Disease Response [3]
Target Regulator Ubiquitin thioesterase OTUB1 (OTUB1) Protein coding
 Regulator Info 
Pathway Response Fatty acid metabolism hsa01212
Ferroptosis hsa04216
Ubiquitin mediated proteolysis hsa04120
Cell Process Cell ferroptosis
In Vitro Model
 mPHs (Mouse primary hepatocytes)
In Vivo Model
ALI induction was performed in 6-8-week-old age-matched C57BL/6J male mice (n = 10-12 per group) by intraperitoneal injection of 3 mL/kg CCl4 in coconut oil. Control and negative control mice were injected with PBS and coconut oil, respectively. At 6 h after injection of CCl4, mice were divided into three groups: CCl4 group, injected with 100 uL PBS (supplemented with 2% mouse serum) through a tail vein; CCl4 + MSC group, injected with 5 x 105 MSCs suspended in 100 uL PBS (supplemented with 2% mouse serum) through a tail vein; CCl4 + Fer-1 group, intraperitoneally injected with ferrostatin-1 (Fer-1, a ferroptosis inhibitor, 2.5 umol/kg body weight). Erastin, intraperitoneal injection of erastin (a ferroptosis inducer, 30 mg/kg body weight) twice every other day, and then the mice were divided into two groups (n = 10-12 per group): Erastin group, injected with 100 uL PBS (supplemented with 2% mouse serum) through a tail vein; Erastin + MSC group, injected with 5 x 105 MSCs suspended in 100 uL PBS (supplemented with 2% mouse serum) through the tail vein.

    Click to Show/Hide
Response regulation MSC-Exo protected against CCl4-induced acute liver injury (ALI) through inhibiting hepatocyte ferroptosis via restoring the SLC7A11 protein level. Additionally, the exosome-induced recovery of SLC7A11 protein was accompanied by upregulations of CD44 and OTUB1.
Health [ICD-11: N.A.]
 Disease Info 
In total 1 item(s) under this disease
Experiment 1 Reporting the Ferroptosis-centered Disease Response [4]
Target Regulator Ubiquitin thioesterase OTUB1 (OTUB1) Protein coding
 Regulator Info 
Pathway Response Fatty acid metabolism hsa01212
Ubiquitin mediated proteolysis hsa04120
Cell Process Cell ferroptosis
In Vitro Model
 HEK293 cells Normal Homo sapiens CVCL_0045
SK-N-BE(2)-C cells Neuroblastoma Homo sapiens CVCL_0529
U2OS cells Osteosarcoma Homo sapiens CVCL_0042
HCT 116 cells Colon carcinoma Homo sapiens CVCL_0291
SK-RC-42 cells Renal cell carcinoma Homo sapiens CVCL_6192
NCI-H1299 cells Lung large cell carcinoma Homo sapiens CVCL_0060
T24 cells Bladder carcinoma Homo sapiens CVCL_0554
UM-UC-3 cells Bladder carcinoma Homo sapiens CVCL_1783
SW780 cells Bladder carcinoma Homo sapiens CVCL_1728
In Vivo Model
5.0 x 106 cells were mixed with Matrigel (BD Biosciences) at 1:1 ratio (v/v) and injected subcutaneously into seven-week old nude mice (NU/NU; Charles River). Mice were fed with regular chow. After nine weeks, the mice were killed and the tumors were weighed and recorded.

    Click to Show/Hide
Response regulation Overexpression of the cancer stem cell marker CD44 enhanced the stability of SLC7A11 by promoting the interaction between SLC7A11 and OTUB1; depletion of CD44 partially abrogated this interaction. CD44 expression suppressed ferroptosis in cancer cells in an OTUB1-dependent manner.
Solasonine [Investigative]
 Drug Info 
In total 1 item(s) under this drug
Experiment 1 Reporting the Ferroptosis-centered Drug Response [1]
Drug for Ferroptosis Inducer
Response Target Cystine/glutamate transporter (SLC7A11) Driver; Suppressor
 Target Info 
Responsed Disease Pancreatic cancer ICD-11: 2C10
 Disease Info 
Pathway Response Fatty acid metabolism hsa01212
Ferroptosis hsa04216
Apoptosis hsa04210
Ubiquitin mediated proteolysis hsa04120
Cell Process Cell ferroptosis
Cell apoptosis
Cell proliferation
Cell migration
Cell invasion
In Vitro Model
 PANC-1 cells Pancreatic ductal adenocarcinoma Homo sapiens CVCL_0480
CFPAC-1 cells Pancreatic ductal adenocarcinoma Homo sapiens CVCL_1119
In Vivo Model
For xenograft assays, we subcutaneously injected 1 x 106 PANC-1 and CFPAC-1 into the right side of each male nude mouse (n = 6). Tumor volumes (length x width2 x 0.5) were measured at specified time points. For one treatment cycle in a week (starting from week 1 to week 5), solasonine (40 or 80 mg/kg, oral administration, 2 times) were given. A total of five treatment cycles were conducted in this experiment.

    Click to Show/Hide
Response regulation Solasonine is involved in ferroptosis by suppressing TFAP2A-mediated transcriptional upregulation of OTUB1, thereby activating ubiquitinated degradation of SLC7A11 and promoting pancreatic cancer cell ferroptosis.
References
Ref 1 Solasonine Inhibits Pancreatic Cancer Progression With Involvement of Ferroptosis Induction. Front Oncol. 2022 Apr 12;12:834729. doi: 10.3389/fonc.2022.834729. eCollection 2022.
Ref 2 A novel circular RNA confers trastuzumab resistance in human epidermal growth factor receptor 2-positive breast cancer through regulating ferroptosis. Environ Toxicol. 2022 Jul;37(7):1597-1607. doi: 10.1002/tox.23509. Epub 2022 Mar 2.
Ref 3 Mesenchymal stem cells protect against ferroptosis via exosome-mediated stabilization of SLC7A11 in acute liver injury. Cell Death Dis. 2022 Mar 26;13(3):271. doi: 10.1038/s41419-022-04708-w.
Ref 4 The Deubiquitylase OTUB1 Mediates Ferroptosis via Stabilization of SLC7A11. Cancer Res. 2019 Apr 15;79(8):1913-1924. doi: 10.1158/0008-5472.CAN-18-3037. Epub 2019 Feb 1.