General Information of the Ferroptosis Regulator (ID: REG10038)
Regulator Name Bromodomain-containing protein 4 (BRD4)
Synonyms
HUNK1; Protein HUNK1
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Gene Name BRD4
Gene ID 23476
Regulator Type Protein coding
Uniprot ID O60885
Sequence
MSAESGPGTRLRNLPVMGDGLETSQMSTTQAQAQPQPANAASTNPPPPETSNPNKPKRQT
NQLQYLLRVVLKTLWKHQFAWPFQQPVDAVKLNLPDYYKIIKTPMDMGTIKKRLENNYYW
NAQECIQDFNTMFTNCYIYNKPGDDIVLMAEALEKLFLQKINELPTEETEIMIVQAKGRG
RGRKETGTAKPGVSTVPNTTQASTPPQTQTPQPNPPPVQATPHPFPAVTPDLIVQTPVMT
VVPPQPLQTPPPVPPQPQPPPAPAPQPVQSHPPIIAATPQPVKTKKGVKRKADTTTPTTI
DPIHEPPSLPPEPKTTKLGQRRESSRPVKPPKKDVPDSQQHPAPEKSSKVSEQLKCCSGI
LKEMFAKKHAAYAWPFYKPVDVEALGLHDYCDIIKHPMDMSTIKSKLEAREYRDAQEFGA
DVRLMFSNCYKYNPPDHEVVAMARKLQDVFEMRFAKMPDEPEEPVVAVSSPAVPPPTKVV
APPSSSDSSSDSSSDSDSSTDDSEEERAQRLAELQEQLKAVHEQLAALSQPQQNKPKKKE
KDKKEKKKEKHKRKEEVEENKKSKAKEPPPKKTKKNNSSNSNVSKKEPAPMKSKPPPTYE
SEEEDKCKPMSYEEKRQLSLDINKLPGEKLGRVVHIIQSREPSLKNSNPDEIEIDFETLK
PSTLRELERYVTSCLRKKRKPQAEKVDVIAGSSKMKGFSSSESESSSESSSSDSEDSETE
MAPKSKKKGHPGREQKKHHHHHHQQMQQAPAPVPQQPPPPPQQPPPPPPPQQQQQPPPPP
PPPSMPQQAAPAMKSSPPPFIATQVPVLEPQLPGSVFDPIGHFTQPILHLPQPELPPHLP
QPPEHSTPPHLNQHAVVSPPALHNALPQQPSRPSNRAAALPPKPARPPAVSPALTQTPLL
PQPPMAQPPQVLLEDEEPPAPPLTSMQMQLYLQQLQKVQPPTPLLPSVKVQSQPPPPLPP
PPHPSVQQQLQQQPPPPPPPQPQPPPQQQHQPPPRPVHLQPMQFSTHIQQPPPPQGQQPP
HPPPGQQPPPPQPAKPQQVIQHHHSPRHHKSDPYSTGHLREAPSPLMIHSPQMSQFQSLT
HQSPPQQNVQPKKQELRAASVVQPQPLVVVKEEKIHSPIIRSEPFSPSLRPEPPKHPESI
KAPVHLPQRPEMKPVDVGRPVIRPPEQNAPPPGAPDKDKQKQEPKTPVAPKKDLKIKNMG
SWASLVQKHPTTPSSTAKSSSDSFEQFRRAAREKEEREKALKAQAEHAEKEKERLRQERM
RSREDEDALEQARRAHEEARRRQEQQQQQRQEQQQQQQQQAAAVAAAATPQAQSSQPQSM
LDQQRELARKREQERRRREAMAATIDMNFQSDLLSIFEENLF

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Function
Chromatin reader protein that recognizes and binds acetylated histones and plays a key role in transmission of epigenetic memory across cell divisions and transcription regulation. Remains associated with acetylated chromatin throughout the entire cell cycle and provides epigenetic memory for postmitotic G1 gene transcription by preserving acetylated chromatin status and maintaining high-order chromatin structure. During interphase, plays a key role in regulating the transcription of signal- inducible genes by associating with the P-TEFb complex and recruiting it to promoters. Also recruits P-TEFb complex to distal enhancers, so called anti-pause enhancers in collaboration with JMJD6. BRD4 and JMJD6 are required to form the transcriptionally active P-TEFb complex by displacing negative regulators such as HEXIM1 and 7SKsnRNA complex from P-TEFb, thereby transforming it into an active form that can then phosphorylate the C-terminal domain (CTD) of RNA polymerase II. Promotes phosphorylation of 'Ser-2' of the C-terminal domain (CTD) of RNA polymerase II. According to a report, directly acts as an atypical protein kinase and mediates phosphorylation of 'Ser-2' of the C-terminal domain (CTD) of RNA polymerase II; these data however need additional evidences in vivo. In addition to acetylated histones, also recognizes and binds acetylated RELA, leading to further recruitment of the P-TEFb complex and subsequent activation of NF-kappa-B. Also acts as a regulator of p53/TP53-mediated transcription: following phosphorylation by CK2, recruited to p53/TP53 specific target promoters.

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HGNC ID
HGNC:13575
KEGG ID hsa:23476
Full List of the Ferroptosis Target of This Regulator and Corresponding Disease/Drug Response(s)
BRD4 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).
Browse Target
Browse Disease
Browse Drug
Phospholipid hydroperoxide glutathione peroxidase (GPX4) [Suppressor]
In total 1 item(s) under this target
Experiment 1 Reporting the Ferroptosis Target of This Regulator [1]
Target for Ferroptosis Suppressor
Responsed Disease Breast cancer ICD-11: 2C60
Responsed Drug JQ1 Investigative
Pathway Response Fatty acid metabolism hsa01212
Ferroptosis hsa04216
Apoptosis hsa04210
Autophagy hsa04140
Cell Process Cell ferroptosis
Cell apoptosis
Cell autophagy
Cell proliferation
Cell migration
Cell invasion
In Vitro Model
MDA-MB-231 cells Breast adenocarcinoma Homo sapiens CVCL_0062
Hs-578T cells Invasive breast carcinoma Homo sapiens CVCL_0332
NCI-H1299 cells Lung large cell carcinoma Homo sapiens CVCL_0060
A-549 cells Lung adenocarcinoma Homo sapiens CVCL_0023
MCF-10A cells Normal Homo sapiens CVCL_0598
In Vivo Model
Female athymic BALB/c nude mice (4-6-week old) were obtained from Beijing Vital River Laboratory Animal Technology Co., Ltd. (Beijing, China). Approximately 1 x 107 cells (A549) in 200 uL of serum-free medium and Matrigel solution were injected directly into the right axilla of each mouse. Tumor growth was measured with calipers every 3 days.

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Response regulation Ferroptosis was induced under (+)-JQ1 treatment and BRD4 knockdown, indicating that (+)-JQ1 induces ferroptosis via BRD4 inhibition in breast adenocarcinoma. In addition, expression of the ferroptosis-associated genes GPX4, SLC7A11, and SLC3A2 was downregulated under (+)-JQ1 treatment. Moreover, JQ1 treatment and BRD4 knockdown led to decreased FTH1 expression.
Ferritin heavy chain (FTH1) [Suppressor; Marker]
In total 1 item(s) under this target
Experiment 1 Reporting the Ferroptosis Target of This Regulator [1]
Target for Ferroptosis Marker/Suppressor
Responsed Disease Breast cancer ICD-11: 2C60
Responsed Drug JQ1 Investigative
Pathway Response Fatty acid metabolism hsa01212
Ferroptosis hsa04216
Apoptosis hsa04210
Autophagy hsa04140
Cell Process Cell ferroptosis
Cell apoptosis
Cell autophagy
Cell proliferation
Cell migration
Cell invasion
In Vitro Model
MDA-MB-231 cells Breast adenocarcinoma Homo sapiens CVCL_0062
Hs-578T cells Invasive breast carcinoma Homo sapiens CVCL_0332
NCI-H1299 cells Lung large cell carcinoma Homo sapiens CVCL_0060
A-549 cells Lung adenocarcinoma Homo sapiens CVCL_0023
MCF-10A cells Normal Homo sapiens CVCL_0598
In Vivo Model
Female athymic BALB/c nude mice (4-6-week old) were obtained from Beijing Vital River Laboratory Animal Technology Co., Ltd. (Beijing, China). Approximately 1 x 107 cells (A549) in 200 uL of serum-free medium and Matrigel solution were injected directly into the right axilla of each mouse. Tumor growth was measured with calipers every 3 days.

    Click to Show/Hide
Response regulation Ferroptosis was induced under (+)-JQ1 treatment and BRD4 knockdown, indicating that (+)-JQ1 induces ferroptosis via BRD4 inhibition in breast adenocarcinoma. In addition, expression of the ferroptosis-associated genes GPX4, SLC7A11, and SLC3A2 was downregulated under (+)-JQ1 treatment. Moreover, JQ1 treatment and BRD4 knockdown led to decreased FTH1 expression.
Cystine/glutamate transporter (SLC7A11) [Driver; Suppressor]
In total 1 item(s) under this target
Experiment 1 Reporting the Ferroptosis Target of This Regulator [1]
Target for Ferroptosis Suppressor
Responsed Disease Breast cancer ICD-11: 2C60
Responsed Drug JQ1 Investigative
Pathway Response Fatty acid metabolism hsa01212
Ferroptosis hsa04216
Apoptosis hsa04210
Autophagy hsa04140
Cell Process Cell ferroptosis
Cell apoptosis
Cell autophagy
Cell proliferation
Cell migration
Cell invasion
In Vitro Model
MDA-MB-231 cells Breast adenocarcinoma Homo sapiens CVCL_0062
Hs-578T cells Invasive breast carcinoma Homo sapiens CVCL_0332
NCI-H1299 cells Lung large cell carcinoma Homo sapiens CVCL_0060
A-549 cells Lung adenocarcinoma Homo sapiens CVCL_0023
MCF-10A cells Normal Homo sapiens CVCL_0598
In Vivo Model
Female athymic BALB/c nude mice (4-6-week old) were obtained from Beijing Vital River Laboratory Animal Technology Co., Ltd. (Beijing, China). Approximately 1 x 107 cells (A549) in 200 uL of serum-free medium and Matrigel solution were injected directly into the right axilla of each mouse. Tumor growth was measured with calipers every 3 days.

    Click to Show/Hide
Response regulation Ferroptosis was induced under (+)-JQ1 treatment and BRD4 knockdown, indicating that (+)-JQ1 induces ferroptosis via BRD4 inhibition in breast adenocarcinoma. In addition, expression of the ferroptosis-associated genes GPX4, SLC7A11, and SLC3A2 was downregulated under (+)-JQ1 treatment. Moreover, JQ1 treatment and BRD4 knockdown led to decreased FTH1 expression.
4F2 cell-surface antigen heavy chain (SLC3A2) [Suppressor]
In total 1 item(s) under this target
Experiment 1 Reporting the Ferroptosis Target of This Regulator [1]
Target for Ferroptosis Suppressor
Responsed Disease Breast cancer ICD-11: 2C60
Responsed Drug JQ1 Investigative
Pathway Response Fatty acid metabolism hsa01212
Ferroptosis hsa04216
Apoptosis hsa04210
Autophagy hsa04140
Cell Process Cell ferroptosis
Cell apoptosis
Cell autophagy
Cell proliferation
Cell migration
Cell invasion
In Vitro Model
MDA-MB-231 cells Breast adenocarcinoma Homo sapiens CVCL_0062
Hs-578T cells Invasive breast carcinoma Homo sapiens CVCL_0332
NCI-H1299 cells Lung large cell carcinoma Homo sapiens CVCL_0060
A-549 cells Lung adenocarcinoma Homo sapiens CVCL_0023
MCF-10A cells Normal Homo sapiens CVCL_0598
In Vivo Model
Female athymic BALB/c nude mice (4-6-week old) were obtained from Beijing Vital River Laboratory Animal Technology Co., Ltd. (Beijing, China). Approximately 1 x 107 cells (A549) in 200 uL of serum-free medium and Matrigel solution were injected directly into the right axilla of each mouse. Tumor growth was measured with calipers every 3 days.

    Click to Show/Hide
Response regulation Ferroptosis was induced under (+)-JQ1 treatment and BRD4 knockdown, indicating that (+)-JQ1 induces ferroptosis via BRD4 inhibition in breast adenocarcinoma. In addition, expression of the ferroptosis-associated genes GPX4, SLC7A11, and SLC3A2 was downregulated under (+)-JQ1 treatment. Moreover, JQ1 treatment and BRD4 knockdown led to decreased FTH1 expression.
Unspecific Target [Unspecific Target]
In total 2 item(s) under this target
Experiment 1 Reporting the Ferroptosis Target of This Regulator [2]
Responsed Disease Breast cancer ICD-11: 2C60
Responsed Drug I-BET151 Investigative
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.
Experiment 2 Reporting the Ferroptosis Target of This Regulator [3]
Responsed Disease Breast cancer ICD-11: 2C60
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, BRDT) and the proteasome applied at low doses could be a promising therapeutic approach for TNBC.
Breast cancer [ICD-11: 2C60]
In total 6 item(s) under this disease
Experiment 1 Reporting the Ferroptosis-centered Disease Response [1]
Target Regulator Bromodomain-containing protein 4 (BRD4) Protein coding
Responsed Drug JQ1 Investigative
Pathway Response Fatty acid metabolism hsa01212
Ferroptosis hsa04216
Apoptosis hsa04210
Autophagy hsa04140
Cell Process Cell ferroptosis
Cell apoptosis
Cell autophagy
Cell proliferation
Cell migration
Cell invasion
In Vitro Model
MDA-MB-231 cells Breast adenocarcinoma Homo sapiens CVCL_0062
Hs-578T cells Invasive breast carcinoma Homo sapiens CVCL_0332
NCI-H1299 cells Lung large cell carcinoma Homo sapiens CVCL_0060
A-549 cells Lung adenocarcinoma Homo sapiens CVCL_0023
MCF-10A cells Normal Homo sapiens CVCL_0598
In Vivo Model
Female athymic BALB/c nude mice (4-6-week old) were obtained from Beijing Vital River Laboratory Animal Technology Co., Ltd. (Beijing, China). Approximately 1 x 107 cells (A549) in 200 uL of serum-free medium and Matrigel solution were injected directly into the right axilla of each mouse. Tumor growth was measured with calipers every 3 days.

    Click to Show/Hide
Response regulation Ferroptosis was induced under (+)-JQ1 treatment and BRD4 knockdown, indicating that (+)-JQ1 induces ferroptosis via BRD4 inhibition in breast adenocarcinoma. In addition, expression of the ferroptosis-associated genes GPX4, SLC7A11, and SLC3A2 was downregulated under (+)-JQ1 treatment. Moreover, JQ1 treatment and BRD4 knockdown led to decreased FTH1 expression.
Experiment 2 Reporting the Ferroptosis-centered Disease Response [1]
Target Regulator Bromodomain-containing protein 4 (BRD4) Protein coding
Responsed Drug JQ1 Investigative
Pathway Response Fatty acid metabolism hsa01212
Ferroptosis hsa04216
Apoptosis hsa04210
Autophagy hsa04140
Cell Process Cell ferroptosis
Cell apoptosis
Cell autophagy
Cell proliferation
Cell migration
Cell invasion
In Vitro Model
MDA-MB-231 cells Breast adenocarcinoma Homo sapiens CVCL_0062
Hs-578T cells Invasive breast carcinoma Homo sapiens CVCL_0332
NCI-H1299 cells Lung large cell carcinoma Homo sapiens CVCL_0060
A-549 cells Lung adenocarcinoma Homo sapiens CVCL_0023
MCF-10A cells Normal Homo sapiens CVCL_0598
In Vivo Model
Female athymic BALB/c nude mice (4-6-week old) were obtained from Beijing Vital River Laboratory Animal Technology Co., Ltd. (Beijing, China). Approximately 1 x 107 cells (A549) in 200 uL of serum-free medium and Matrigel solution were injected directly into the right axilla of each mouse. Tumor growth was measured with calipers every 3 days.

    Click to Show/Hide
Response regulation Ferroptosis was induced under (+)-JQ1 treatment and BRD4 knockdown, indicating that (+)-JQ1 induces ferroptosis via BRD4 inhibition in breast adenocarcinoma. In addition, expression of the ferroptosis-associated genes GPX4, SLC7A11, and SLC3A2 was downregulated under (+)-JQ1 treatment. Moreover, JQ1 treatment and BRD4 knockdown led to decreased FTH1 expression.
Experiment 3 Reporting the Ferroptosis-centered Disease Response [1]
Target Regulator Bromodomain-containing protein 4 (BRD4) Protein coding
Responsed Drug JQ1 Investigative
Pathway Response Fatty acid metabolism hsa01212
Ferroptosis hsa04216
Apoptosis hsa04210
Autophagy hsa04140
Cell Process Cell ferroptosis
Cell apoptosis
Cell autophagy
Cell proliferation
Cell migration
Cell invasion
In Vitro Model
MDA-MB-231 cells Breast adenocarcinoma Homo sapiens CVCL_0062
Hs-578T cells Invasive breast carcinoma Homo sapiens CVCL_0332
NCI-H1299 cells Lung large cell carcinoma Homo sapiens CVCL_0060
A-549 cells Lung adenocarcinoma Homo sapiens CVCL_0023
MCF-10A cells Normal Homo sapiens CVCL_0598
In Vivo Model
Female athymic BALB/c nude mice (4-6-week old) were obtained from Beijing Vital River Laboratory Animal Technology Co., Ltd. (Beijing, China). Approximately 1 x 107 cells (A549) in 200 uL of serum-free medium and Matrigel solution were injected directly into the right axilla of each mouse. Tumor growth was measured with calipers every 3 days.

    Click to Show/Hide
Response regulation Ferroptosis was induced under (+)-JQ1 treatment and BRD4 knockdown, indicating that (+)-JQ1 induces ferroptosis via BRD4 inhibition in breast adenocarcinoma. In addition, expression of the ferroptosis-associated genes GPX4, SLC7A11, and SLC3A2 was downregulated under (+)-JQ1 treatment. Moreover, JQ1 treatment and BRD4 knockdown led to decreased FTH1 expression.
Experiment 4 Reporting the Ferroptosis-centered Disease Response [1]
Target Regulator Bromodomain-containing protein 4 (BRD4) Protein coding
Responsed Drug JQ1 Investigative
Pathway Response Fatty acid metabolism hsa01212
Ferroptosis hsa04216
Apoptosis hsa04210
Autophagy hsa04140
Cell Process Cell ferroptosis
Cell apoptosis
Cell autophagy
Cell proliferation
Cell migration
Cell invasion
In Vitro Model
MDA-MB-231 cells Breast adenocarcinoma Homo sapiens CVCL_0062
Hs-578T cells Invasive breast carcinoma Homo sapiens CVCL_0332
NCI-H1299 cells Lung large cell carcinoma Homo sapiens CVCL_0060
A-549 cells Lung adenocarcinoma Homo sapiens CVCL_0023
MCF-10A cells Normal Homo sapiens CVCL_0598
In Vivo Model
Female athymic BALB/c nude mice (4-6-week old) were obtained from Beijing Vital River Laboratory Animal Technology Co., Ltd. (Beijing, China). Approximately 1 x 107 cells (A549) in 200 uL of serum-free medium and Matrigel solution were injected directly into the right axilla of each mouse. Tumor growth was measured with calipers every 3 days.

    Click to Show/Hide
Response regulation Ferroptosis was induced under (+)-JQ1 treatment and BRD4 knockdown, indicating that (+)-JQ1 induces ferroptosis via BRD4 inhibition in breast adenocarcinoma. In addition, expression of the ferroptosis-associated genes GPX4, SLC7A11, and SLC3A2 was downregulated under (+)-JQ1 treatment. Moreover, JQ1 treatment and BRD4 knockdown led to decreased FTH1 expression.
Experiment 5 Reporting the Ferroptosis-centered Disease Response [2]
Target Regulator Bromodomain-containing protein 4 (BRD4) Protein coding
Responsed Drug I-BET151 Investigative
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.
Experiment 6 Reporting the Ferroptosis-centered Disease Response [3]
Target Regulator Bromodomain-containing protein 4 (BRD4) Protein coding
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, BRDT) and the proteasome applied at low doses could be a promising therapeutic approach for TNBC.
JQ1 [Investigative]
In total 4 item(s) under this drug
Experiment 1 Reporting the Ferroptosis-centered Drug Response [1]
Drug for Ferroptosis Inducer
Response Target Phospholipid hydroperoxide glutathione peroxidase (GPX4) Suppressor
Responsed Disease Breast cancer ICD-11: 2C60
Pathway Response Fatty acid metabolism hsa01212
Ferroptosis hsa04216
Apoptosis hsa04210
Autophagy hsa04140
Cell Process Cell ferroptosis
Cell apoptosis
Cell autophagy
Cell proliferation
Cell migration
Cell invasion
In Vitro Model
MDA-MB-231 cells Breast adenocarcinoma Homo sapiens CVCL_0062
Hs-578T cells Invasive breast carcinoma Homo sapiens CVCL_0332
NCI-H1299 cells Lung large cell carcinoma Homo sapiens CVCL_0060
A-549 cells Lung adenocarcinoma Homo sapiens CVCL_0023
MCF-10A cells Normal Homo sapiens CVCL_0598
In Vivo Model
Female athymic BALB/c nude mice (4-6-week old) were obtained from Beijing Vital River Laboratory Animal Technology Co., Ltd. (Beijing, China). Approximately 1 x 107 cells (A549) in 200 uL of serum-free medium and Matrigel solution were injected directly into the right axilla of each mouse. Tumor growth was measured with calipers every 3 days.

    Click to Show/Hide
Response regulation Ferroptosis was induced under (+)-JQ1 treatment and BRD4 knockdown, indicating that (+)-JQ1 induces ferroptosis via BRD4 inhibition in breast adenocarcinoma. In addition, expression of the ferroptosis-associated genes GPX4, SLC7A11, and SLC3A2 was downregulated under (+)-JQ1 treatment. Moreover, JQ1 treatment and BRD4 knockdown led to decreased FTH1 expression.
Experiment 2 Reporting the Ferroptosis-centered Drug Response [1]
Drug for Ferroptosis Inducer
Response Target Ferritin heavy chain (FTH1) Suppressor; Marker
Responsed Disease Breast cancer ICD-11: 2C60
Pathway Response Fatty acid metabolism hsa01212
Ferroptosis hsa04216
Apoptosis hsa04210
Autophagy hsa04140
Cell Process Cell ferroptosis
Cell apoptosis
Cell autophagy
Cell proliferation
Cell migration
Cell invasion
In Vitro Model
MDA-MB-231 cells Breast adenocarcinoma Homo sapiens CVCL_0062
Hs-578T cells Invasive breast carcinoma Homo sapiens CVCL_0332
NCI-H1299 cells Lung large cell carcinoma Homo sapiens CVCL_0060
A-549 cells Lung adenocarcinoma Homo sapiens CVCL_0023
MCF-10A cells Normal Homo sapiens CVCL_0598
In Vivo Model
Female athymic BALB/c nude mice (4-6-week old) were obtained from Beijing Vital River Laboratory Animal Technology Co., Ltd. (Beijing, China). Approximately 1 x 107 cells (A549) in 200 uL of serum-free medium and Matrigel solution were injected directly into the right axilla of each mouse. Tumor growth was measured with calipers every 3 days.

    Click to Show/Hide
Response regulation Ferroptosis was induced under (+)-JQ1 treatment and BRD4 knockdown, indicating that (+)-JQ1 induces ferroptosis via BRD4 inhibition in breast adenocarcinoma. In addition, expression of the ferroptosis-associated genes GPX4, SLC7A11, and SLC3A2 was downregulated under (+)-JQ1 treatment. Moreover, JQ1 treatment and BRD4 knockdown led to decreased FTH1 expression.
Experiment 3 Reporting the Ferroptosis-centered Drug Response [1]
Drug for Ferroptosis Inducer
Response Target Cystine/glutamate transporter (SLC7A11) Driver; Suppressor
Responsed Disease Breast cancer ICD-11: 2C60
Pathway Response Fatty acid metabolism hsa01212
Ferroptosis hsa04216
Apoptosis hsa04210
Autophagy hsa04140
Cell Process Cell ferroptosis
Cell apoptosis
Cell autophagy
Cell proliferation
Cell migration
Cell invasion
In Vitro Model
MDA-MB-231 cells Breast adenocarcinoma Homo sapiens CVCL_0062
Hs-578T cells Invasive breast carcinoma Homo sapiens CVCL_0332
NCI-H1299 cells Lung large cell carcinoma Homo sapiens CVCL_0060
A-549 cells Lung adenocarcinoma Homo sapiens CVCL_0023
MCF-10A cells Normal Homo sapiens CVCL_0598
In Vivo Model
Female athymic BALB/c nude mice (4-6-week old) were obtained from Beijing Vital River Laboratory Animal Technology Co., Ltd. (Beijing, China). Approximately 1 x 107 cells (A549) in 200 uL of serum-free medium and Matrigel solution were injected directly into the right axilla of each mouse. Tumor growth was measured with calipers every 3 days.

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Response regulation Ferroptosis was induced under (+)-JQ1 treatment and BRD4 knockdown, indicating that (+)-JQ1 induces ferroptosis via BRD4 inhibition in breast adenocarcinoma. In addition, expression of the ferroptosis-associated genes GPX4, SLC7A11, and SLC3A2 was downregulated under (+)-JQ1 treatment. Moreover, JQ1 treatment and BRD4 knockdown led to decreased FTH1 expression.
Experiment 4 Reporting the Ferroptosis-centered Drug Response [1]
Drug for Ferroptosis Inducer
Response Target 4F2 cell-surface antigen heavy chain (SLC3A2) Suppressor
Responsed Disease Breast cancer ICD-11: 2C60
Pathway Response Fatty acid metabolism hsa01212
Ferroptosis hsa04216
Apoptosis hsa04210
Autophagy hsa04140
Cell Process Cell ferroptosis
Cell apoptosis
Cell autophagy
Cell proliferation
Cell migration
Cell invasion
In Vitro Model
MDA-MB-231 cells Breast adenocarcinoma Homo sapiens CVCL_0062
Hs-578T cells Invasive breast carcinoma Homo sapiens CVCL_0332
NCI-H1299 cells Lung large cell carcinoma Homo sapiens CVCL_0060
A-549 cells Lung adenocarcinoma Homo sapiens CVCL_0023
MCF-10A cells Normal Homo sapiens CVCL_0598
In Vivo Model
Female athymic BALB/c nude mice (4-6-week old) were obtained from Beijing Vital River Laboratory Animal Technology Co., Ltd. (Beijing, China). Approximately 1 x 107 cells (A549) in 200 uL of serum-free medium and Matrigel solution were injected directly into the right axilla of each mouse. Tumor growth was measured with calipers every 3 days.

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Response regulation Ferroptosis was induced under (+)-JQ1 treatment and BRD4 knockdown, indicating that (+)-JQ1 induces ferroptosis via BRD4 inhibition in breast adenocarcinoma. In addition, expression of the ferroptosis-associated genes GPX4, SLC7A11, and SLC3A2 was downregulated under (+)-JQ1 treatment. Moreover, JQ1 treatment and BRD4 knockdown led to decreased FTH1 expression.
I-BET151 [Investigative]
In total 1 item(s) under this drug
Experiment 1 Reporting the Ferroptosis-centered Drug Response [2]
Drug for Ferroptosis Inducer
Response Target Unspecific Target
Responsed Disease Breast cancer ICD-11: 2C60
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.
References
Ref 1 Ferritinophagy is required for the induction of ferroptosis by the bromodomain protein BRD4 inhibitor (+)-JQ1 in cancer cells. Cell Death Dis. 2019 Apr 15;10(5):331. doi: 10.1038/s41419-019-1564-7.
Ref 2 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 3 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.