Ferroptosis Regulator Information

General Information of the Ferroptosis Regulator (ID: REG10242)
Regulator Name Bromodomain testis-specific protein (BRDT)
Synonyms
Cancer/testis antigen 9; RING3-like protein
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Gene Name BRDT
Gene ID 676
Regulator Type Protein coding
Uniprot ID Q58F21
Sequence
MSLPSRQTAIIVNPPPPEYINTKKNGRLTNQLQYLQKVVLKDLWKHSFSWPFQRPVDAVK
LQLPDYYTIIKNPMDLNTIKKRLENKYYAKASECIEDFNTMFSNCYLYNKPGDDIVLMAQ
ALEKLFMQKLSQMPQEEQVVGVKERIKKGTQQNIAVSSAKEKSSPSATEKVFKQQEIPSV
FPKTSISPLNVVQGASVNSSSQTAAQVTKGVKRKADTTTPATSAVKASSEFSPTFTEKSV
ALPPIKENMPKNVLPDSQQQYNVVKTVKVTEQLRHCSEILKEMLAKKHFSYAWPFYNPVD
VNALGLHNYYDVVKNPMDLGTIKEKMDNQEYKDAYKFAADVRLMFMNCYKYNPPDHEVVT
MARMLQDVFETHFSKIPIEPVESMPLCYIKTDITETTGRENTNEASSEGNSSDDSEDERV
KRLAKLQEQLKAVHQQLQVLSQVPFRKLNKKKEKSKKEKKKEKVNNSNENPRKMCEQMRL
KEKSKRNQPKKRKQQFIGLKSEDEDNAKPMNYDEKRQLSLNINKLPGDKLGRVVHIIQSR
EPSLSNSNPDEIEIDFETLKASTLRELEKYVSACLRKRPLKPPAKKIMMSKEELHSQKKQ
ELEKRLLDVNNQLNSRKRQTKSDKTQPSKAVENVSRLSESSSSSSSSSESESSSSDLSSS
DSSDSESEMFPKFTEVKPNDSPSKENVKKMKNECIPPEGRTGVTQIGYCVQDTTSANTTL
VHQTTPSHVMPPNHHQLAFNYQELEHLQTVKNISPLQILPPSGDSEQLSNGITVMHPSGD
SDTTMLESECQAPVQKDIKIKNADSWKSLGKPVKPSGVMKSSDELFNQFRKAAIEKEVKA
RTQELIRKHLEQNTKELKASQENQRDLGNGLTVESFSNKIQNKCSGEEQKEHQQSSEAQD
KSKLWLLKDRDLARQKEQERRRREAMVGTIDMTLQSDIMTMFENNFD

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Function
Testis-specific chromatin protein that specifically binds histone H4 acetylated at 'Lys-5' and 'Lys-8' (H4K5ac and H4K8ac, respectively) and plays a key role in spermatogenesis. Required in late pachytene spermatocytes: plays a role in meiotic and post-meiotic cells by binding to acetylated histones at the promoter of specific meiotic and post-meiotic genes, facilitating their activation at the appropriate time. In the post-meiotic phase of spermatogenesis, binds to hyperacetylated histones and participates in their general removal from DNA. Also recognizes and binds a subset of butyrylated histones: able to bind histone H4 butyrylated at 'Lys-8' (H4K8ac), while it is not able to bind H4 butyrylated at 'Lys-5' (H4K5ac). Also acts as a component of the splicing machinery in pachytene spermatocytes and round spermatids and participates in 3'-UTR truncation of specific mRNAs in post-meiotic spermatids. Required for chromocenter organization, a structure comprised of peri-centromeric heterochromatin.

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HGNC ID
HGNC:1105
KEGG ID hsa:676
Full List of the Ferroptosis Target of This Regulator and Corresponding Disease/Drug Response(s)
BRDT 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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Unspecific Target [Unspecific Target]
In total 2 item(s) under this target
Experiment 1 Reporting the Ferroptosis Target of This Regulator [1]
Responsed Disease Breast cancer ICD-11: 2C60
 Disease Info 
Responsed Drug I-BET151 Investigative
 Drug Info 
Pathway Response Fatty acid metabolism hsa01212
Ferroptosis hsa04216
Cell Process Cell ferroptosis
Cell proliferation
In Vitro Model
 MDA-MB-231 cells Breast adenocarcinoma Homo sapiens CVCL_0062
MDA-MB-468 cells Breast adenocarcinoma Homo sapiens CVCL_0419
SK-BR-3 cells Breast adenocarcinoma Homo sapiens CVCL_0033
In Vivo Model
Athymic nu/nu mice (5 to 6-week-old female) were acquired from the Silaike Experimental Animal Co. Ltd (Shanghai, China). All mice were randomly allocated to different groups, 1 x 106 MDA-MB-231 cells were subcutaneously inoculated into the right flanks. Ten days later, mice were intraperitoneally injected with PBS including DMSO, JQ1 (50 mg/kg), Bufalin (1 mg/kg) and SR1848 (50 mg/kg), every 2-4 days for 8 times, and the tumor volumes and mice weigh were monitored and recorded every 2-3 days.

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Response regulation BET (BRD2, BRD3, BRD4, BRDT) inhibitors (BETi) exert an excellent anti-cancer activity in breast cancer. BETi JQ1 and I-BET151 exhibited anti-cancer effects in breast cancer by inducing ferroptosis. NCOA3 as a coactivator synergized with NR5A2 to prevent BETi-induced ferroptosis. Mechanistically, NR5A2 synergized with NCOA3 to increase expression of NRF2, a transcription factor that controls the expression of many antioxidant genes.
Experiment 2 Reporting the Ferroptosis Target of This Regulator [2]
Responsed Disease Breast cancer ICD-11: 2C60
 Disease Info 
Pathway Response Fatty acid metabolism hsa01212
Ferroptosis hsa04216
Cell Process Cell ferroptosis
In Vitro Model
 MCF-10A cells Normal Homo sapiens CVCL_0598
HEK-293T cells Normal Homo sapiens CVCL_0063
HCC38 cells Breast ductal carcinoma Homo sapiens CVCL_1267
MDA-MB-468 cells Breast adenocarcinoma Homo sapiens CVCL_0419
HCC1143 cells Breast ductal carcinoma Homo sapiens CVCL_1245
HCC1937 cells Breast ductal carcinoma Homo sapiens CVCL_0290
HCC70 cells Breast ductal carcinoma Homo sapiens CVCL_1270
HCC38 cells Breast ductal carcinoma Homo sapiens CVCL_1267
MDA-MB-231 cells Breast adenocarcinoma Homo sapiens CVCL_0062
BT-549 cells Invasive breast carcinoma Homo sapiens CVCL_1092
SUM159 cells Breast pleomorphic carcinoma Homo sapiens CVCL_5423
Hs-578T cells Invasive breast carcinoma Homo sapiens CVCL_0332
In Vivo Model
For mouse xenograft models, MDA-MB-231 cells (2 x 106 per mouse) expressing green fluorescent protein (GFP) luciferase were implanted bilaterally into the fat pads of the fourth inguinal mammary gland of 6-week-old female athymic nude-Foxn1nu mice. Twenty-three days later, mice were randomized into four groups (n = 10 mice per group) and treated with the following: (i) vehicle; (ii) OTX015, daily through oral gavage (25 mg/kg); OTX015 (100 mg/ml stock in DMSO) was diluted in vehicle solution containing 2% DMSO, 30% polyethylene glycol (PEG)300, and 5% Tween 80; (iii) SB225022, which was intraperitoneally administered 5 days a week, at 5 mg/kg prepared in PBS; or (iv) OTX015 + SB225022 combination.

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Response regulation BRD4 transcript and protein levels are highly enriched in triple-negative breast cancer tumors and cell lines. Cotargeting of BET (BRD2, BRD3, BRD4, B RDT) and the proteasome applied at low doses could be a promising therapeutic approach for TNBC.
Breast cancer [ICD-11: 2C60]
 Disease Info 
In total 2 item(s) under this disease
Experiment 1 Reporting the Ferroptosis-centered Disease Response [1]
Target Regulator Bromodomain testis-specific protein (BRDT) Protein coding
 Regulator Info 
Responsed Drug I-BET151 Investigative
 Drug Info 
Pathway Response Fatty acid metabolism hsa01212
Ferroptosis hsa04216
Cell Process Cell ferroptosis
Cell proliferation
In Vitro Model
 MDA-MB-231 cells Breast adenocarcinoma Homo sapiens CVCL_0062
MDA-MB-468 cells Breast adenocarcinoma Homo sapiens CVCL_0419
SK-BR-3 cells Breast adenocarcinoma Homo sapiens CVCL_0033
In Vivo Model
Athymic nu/nu mice (5 to 6-week-old female) were acquired from the Silaike Experimental Animal Co. Ltd (Shanghai, China). All mice were randomly allocated to different groups, 1 x 106 MDA-MB-231 cells were subcutaneously inoculated into the right flanks. Ten days later, mice were intraperitoneally injected with PBS including DMSO, JQ1 (50 mg/kg), Bufalin (1 mg/kg) and SR1848 (50 mg/kg), every 2-4 days for 8 times, and the tumor volumes and mice weigh were monitored and recorded every 2-3 days.

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Response regulation BET (BRD2, BRD3, BRD4, BRDT) inhibitors (BETi) exert an excellent anti-cancer activity in breast cancer. BETi JQ1 and I-BET151 exhibited anti-cancer effects in breast cancer by inducing ferroptosis. NCOA3 as a coactivator synergized with NR5A2 to prevent BETi-induced ferroptosis. Mechanistically, NR5A2 synergized with NCOA3 to increase expression of NRF2, a transcription factor that controls the expression of many antioxidant genes.
Experiment 2 Reporting the Ferroptosis-centered Disease Response [2]
Target Regulator Bromodomain testis-specific protein (BRDT) Protein coding
 Regulator Info 
Pathway Response Fatty acid metabolism hsa01212
Ferroptosis hsa04216
Cell Process Cell ferroptosis
In Vitro Model
 MCF-10A cells Normal Homo sapiens CVCL_0598
HEK-293T cells Normal Homo sapiens CVCL_0063
HCC38 cells Breast ductal carcinoma Homo sapiens CVCL_1267
MDA-MB-468 cells Breast adenocarcinoma Homo sapiens CVCL_0419
HCC1143 cells Breast ductal carcinoma Homo sapiens CVCL_1245
HCC1937 cells Breast ductal carcinoma Homo sapiens CVCL_0290
HCC70 cells Breast ductal carcinoma Homo sapiens CVCL_1270
HCC38 cells Breast ductal carcinoma Homo sapiens CVCL_1267
MDA-MB-231 cells Breast adenocarcinoma Homo sapiens CVCL_0062
BT-549 cells Invasive breast carcinoma Homo sapiens CVCL_1092
SUM159 cells Breast pleomorphic carcinoma Homo sapiens CVCL_5423
Hs-578T cells Invasive breast carcinoma Homo sapiens CVCL_0332
In Vivo Model
For mouse xenograft models, MDA-MB-231 cells (2 x 106 per mouse) expressing green fluorescent protein (GFP) luciferase were implanted bilaterally into the fat pads of the fourth inguinal mammary gland of 6-week-old female athymic nude-Foxn1nu mice. Twenty-three days later, mice were randomized into four groups (n = 10 mice per group) and treated with the following: (i) vehicle; (ii) OTX015, daily through oral gavage (25 mg/kg); OTX015 (100 mg/ml stock in DMSO) was diluted in vehicle solution containing 2% DMSO, 30% polyethylene glycol (PEG)300, and 5% Tween 80; (iii) SB225022, which was intraperitoneally administered 5 days a week, at 5 mg/kg prepared in PBS; or (iv) OTX015 + SB225022 combination.

    Click to Show/Hide
Response regulation BRD4 transcript and protein levels are highly enriched in triple-negative breast cancer tumors and cell lines. Cotargeting of BET (BRD2, BRD3, BRD4, B RDT) and the proteasome applied at low doses could be a promising therapeutic approach for TNBC.
I-BET151 [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 Unspecific Target
Responsed Disease Breast cancer ICD-11: 2C60
 Disease Info 
Pathway Response Fatty acid metabolism hsa01212
Ferroptosis hsa04216
Cell Process Cell ferroptosis
Cell proliferation
In Vitro Model
 MDA-MB-231 cells Breast adenocarcinoma Homo sapiens CVCL_0062
MDA-MB-468 cells Breast adenocarcinoma Homo sapiens CVCL_0419
SK-BR-3 cells Breast adenocarcinoma Homo sapiens CVCL_0033
In Vivo Model
Athymic nu/nu mice (5 to 6-week-old female) were acquired from the Silaike Experimental Animal Co. Ltd (Shanghai, China). All mice were randomly allocated to different groups, 1 x 106 MDA-MB-231 cells were subcutaneously inoculated into the right flanks. Ten days later, mice were intraperitoneally injected with PBS including DMSO, JQ1 (50 mg/kg), Bufalin (1 mg/kg) and SR1848 (50 mg/kg), every 2-4 days for 8 times, and the tumor volumes and mice weigh were monitored and recorded every 2-3 days.

    Click to Show/Hide
Response regulation BET (BRD2, BRD3, BRD4, BRDT) inhibitors (BETi) exert an excellent anti-cancer activity in breast cancer. BETi JQ1 and I-BET151 exhibited anti-cancer effects in breast cancer by inducing ferroptosis. NCOA3 as a coactivator synergized with NR5A2 to prevent BETi-induced ferroptosis. Mechanistically, NR5A2 synergized with NCOA3 to increase expression of NRF2, a transcription factor that controls the expression of many antioxidant genes.
References
Ref 1 NR5A2 synergizes with NCOA3 to induce breast cancer resistance to BET inhibitor by upregulating NRF2 to attenuate ferroptosis. Biochem Biophys Res Commun. 2020 Sep 17;530(2):402-409. doi: 10.1016/j.bbrc.2020.05.069. Epub 2020 Jun 11.
Ref 2 Synthetic lethal combination targeting BET uncovered intrinsic susceptibility of TNBC to ferroptosis. Sci Adv. 2020 Aug 21;6(34):eaba8968. doi: 10.1126/sciadv.aba8968. Print 2020 Aug.