Ferroptosis Regulator Information

General Information of the Ferroptosis Regulator (ID: REG10224)
Regulator Name Histone-lysine N-methyltransferase EZH2 (EZH2)
Synonyms
KMT6; ENX-1; Enhancer of zeste homolog 2; Lysine N-methyltransferase 6
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Gene Name EZH2
Gene ID 2146
Regulator Type Protein coding
Uniprot ID Q15910
Sequence
MGQTGKKSEKGPVCWRKRVKSEYMRLRQLKRFRRADEVKSMFSSNRQKILERTEILNQEW
KQRRIQPVHILTSVSSLRGTRECSVTSDLDFPTQVIPLKTLNAVASVPIMYSWSPLQQNF
MVEDETVLHNIPYMGDEVLDQDGTFIEELIKNYDGKVHGDRECGFINDEIFVELVNALGQ
YNDDDDDDDGDDPEEREEKQKDLEDHRDDKESRPPRKFPSDKIFEAISSMFPDKGTAEEL
KEKYKELTEQQLPGALPPECTPNIDGPNAKSVQREQSLHSFHTLFCRRCFKYDCFLHPFH
ATPNTYKRKNTETALDNKPCGPQCYQHLEGAKEFAAALTAERIKTPPKRPGGRRRGRLPN
NSSRPSTPTINVLESKDTDSDREAGTETGGENNDKEEEEKKDETSSSSEANSRCQTPIKM
KPNIEPPENVEWSGAEASMFRVLIGTYYDNFCAIARLIGTKTCRQVYEFRVKESSIIAPA
PAEDVDTPPRKKKRKHRLWAAHCRKIQLKKDGSSNHVYNYQPCDHPRQPCDSSCPCVIAQ
NFCEKFCQCSSECQNRFPGCRCKAQCNTKQCPCYLAVRECDPDLCLTCGAADHWDSKNVS
CKNCSIQRGSKKHLLLAPSDVAGWGIFIKDPVQKNEFISEYCGEIISQDEADRRGKVYDK
YMCSFLFNLNNDFVVDATRKGNKIRFANHSVNPNCYAKVMMVNGDHRIGIFAKRAIQTGE
ELFFDYRYSQADALKYVGIEREMEIP

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Family Histone-lysine methyltransferase family
Function
Polycomb group (PcG) protein. Catalytic subunit of the PRC2/EED-EZH2 complex, which methylates 'Lys-9' (H3K9me) and 'Lys-27' (H3K27me) of histone H3, leading to transcriptional repression of the affected target gene. Able to mono-, di- and trimethylate 'Lys-27' of histone H3 to form H3K27me1, H3K27me2 and H3K27me3, respectively. Displays a preference for substrates with less methylation, loses activity when progressively more methyl groups are incorporated into H3K27, H3K27me0 > H3K27me1 > H3K27me2. Compared to EZH1-containing complexes, it is more abundant in embryonic stem cells and plays a major role in forming H3K27me3, which is required for embryonic stem cell identity and proper differentiation. The PRC2/EED-EZH2 complex may also serve as a recruiting platform for DNA methyltransferases, thereby linking two epigenetic repression systems. Genes repressed by the PRC2/EED-EZH2 complex include HOXC8, HOXA9, MYT1, CDKN2A and retinoic acid target genes. EZH2 can also methylate non-histone proteins such as the transcription factor GATA4 and the nuclear receptor RORA. Regulates the circadian clock via histone methylation at the promoter of the circadian genes. Essential for the CRY1/2-mediated repression of the transcriptional activation of PER1/2 by the CLOCK-BMAL1 heterodimer; involved in the di and trimethylation of 'Lys-27' of histone H3 on PER1/2 promoters which is necessary for the CRY1/2 proteins to inhibit transcription.

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HGNC ID
HGNC:3527
KEGG ID hsa:2146
Full List of the Ferroptosis Target of This Regulator and Corresponding Disease/Drug Response(s)
EZH2 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
Transferrin receptor protein 1 (TFRC) [Driver; Suppressor; Marker]
 Target Info 
In total 1 item(s) under this target
Experiment 1 Reporting the Ferroptosis Target of This Regulator [1]
Target for Ferroptosis Marker/Suppressor/Driver
Responsed Disease Diffuse large B-cell lymphoma ICD-11: 2A81
 Disease Info 
Pathway Response Fatty acid metabolism hsa01212
Ferroptosis hsa04216
Cell Process Cell ferroptosis
Cell proliferation
In Vitro Model
 Karpas-422 cells Diffuse large B-cell lymphoma Homo sapiens CVCL_1325
U-2932 cells Diffuse large B-cell lymphoma Homo sapiens CVCL_1896
WILL-2 cells Diffuse large B-cell lymphoma Homo sapiens CVCL_1901
HEK-293T cells Normal Homo sapiens CVCL_0063
In Vivo Model
All animal experiments were approved by the Institutional Animal Care and Use Committee of Shanghai Institute of Materia Medica and performed in accordance with the Association for Assessment and Accreditation of Laboratory Animal Care. Tumors were measured twice weekly and volumes were calculated using the formula TV=length x width2 x 1/2.

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Response regulation EZH2 inhibition upregulated-TfR-1 dysregulation leads to drug resistance in EZH2 WT diffuse large B-cell lymphoma (DLBCL). On the other hand, EZH2i impaired the occurrence of ferroptosis by upregulating the heat shock protein family A (Hsp70) member 5 (HSPA5) and stabilizing glutathione peroxidase 4 (GPX4), a ferroptosis suppressor.
Phospholipid hydroperoxide glutathione peroxidase (GPX4) [Suppressor]
 Target Info 
In total 1 item(s) under this target
Experiment 1 Reporting the Ferroptosis Target of This Regulator [1]
Target for Ferroptosis Suppressor
Responsed Disease Diffuse large B-cell lymphoma ICD-11: 2A81
 Disease Info 
Pathway Response Fatty acid metabolism hsa01212
Ferroptosis hsa04216
Cell Process Cell ferroptosis
Cell proliferation
In Vitro Model
 Karpas-422 cells Diffuse large B-cell lymphoma Homo sapiens CVCL_1325
U-2932 cells Diffuse large B-cell lymphoma Homo sapiens CVCL_1896
WILL-2 cells Diffuse large B-cell lymphoma Homo sapiens CVCL_1901
HEK-293T cells Normal Homo sapiens CVCL_0063
In Vivo Model
All animal experiments were approved by the Institutional Animal Care and Use Committee of Shanghai Institute of Materia Medica and performed in accordance with the Association for Assessment and Accreditation of Laboratory Animal Care. Tumors were measured twice weekly and volumes were calculated using the formula TV=length x width2 x 1/2.

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Response regulation EZH2 inhibition upregulated-TfR-1 dysregulation leads to drug resistance in EZH2 WT diffuse large B-cell lymphoma (DLBCL). On the other hand, EZH2i impaired the occurrence of ferroptosis by upregulating the heat shock protein family A (Hsp70) member 5 (HSPA5) and stabilizing glutathione peroxidase 4 (GPX4), a ferroptosis suppressor.
Cystine/glutamate transporter (SLC7A11) [Driver; Suppressor]
 Target Info 
In total 3 item(s) under this target
Experiment 1 Reporting the Ferroptosis Target of This Regulator [2]
Target for Ferroptosis Suppressor
Responsed Disease Oral squamous cell carcinoma ICD-11: 2B6E
 Disease Info 
Pathway Response Fatty acid metabolism hsa01212
Ferroptosis hsa04216
Cell Process Cell ferroptosis
In Vitro Model
 Tca8113 cells Endocervical adenocarcinoma Homo sapiens CVCL_6851
TSCCA cells Endocervical adenocarcinoma Homo sapiens CVCL_VL15
CAL-27 cells Tongue adenosquamous carcinom Homo sapiens CVCL_1107
SCC-9 cells Tongue squamous cell carcinoma Homo sapiens CVCL_1685
hTECs (Human tongue epithelial cells)
Response regulation EZH2 inhibits the ferroptosis of tongue squamous cell carcinoma cells by inhibiting miR-125b-5p and enhancing SLC7A11. MiR-125b-5p regulates ferroptosis in TSCC cells by targeting SLC7A11.
Experiment 2 Reporting the Ferroptosis Target of This Regulator [3]
Target for Ferroptosis Suppressor
Responsed Disease Multiple sclerosis ICD-11: 8A40
 Disease Info 
Pathway Response Fatty acid metabolism hsa01212
Ferroptosis hsa04216
Cell Process Cell ferroptosis
In Vitro Model
 hBMSCs (Bone marrow stromal cells)
BV-2 cells Normal Mus musculus CVCL_0182
In Vivo Model
Female C57BL6 mice were randomized into four groups (n = 8/group): the control group (non-EAE mice), the EAE group (EAE mice injected intrathecally with 5 uL PBS when symptoms appeared), the EAE + BMSCs-Exo + mimic negative control (NC) group (EAE mice injected intrathecally with Exos from bone MSCs (BMSCs) transfected with mimic NC [5 uL, 2 ug/L in PBS] when symptoms appeared), and the EAE + BMSCs-Exo + miR-367-3p mimic group (EAE mice injected intrathecally with Exos from BMSCs transfected with miR-367-3p mimic [5 uL, 2 ug/L in PBS] when symptoms appeared).

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Response regulation MiR-367-3p can be delivered by BMSC-Exos into microglia, where miR-367-3p inhibits EZH2 expression and activates the expression of SLC7A11, suppressing microglial ferroptosis and relieving the symptoms of EAE. Experimental autoimmune encephalomyelitis (EAE) is a typical animal model of multiple sclerosis.
Experiment 3 Reporting the Ferroptosis Target of This Regulator [4]
Target for Ferroptosis Suppressor
Responsed Disease Hepatoblastoma ICD-11: DB91
 Disease Info 
Pathway Response Fatty acid metabolism hsa01212
Ferroptosis hsa04216
Cell Process Cell ferroptosis
In Vitro Model
 hLCs (Liver cells)
mPHs (Mouse primary hepatocytes)
In Vivo Model
Male C57BL/6 mice (n = 20, 6-8-week-old, b.w. 18-23 g) were purchased from SJA Laboratory Animal Co Ltd., Changsha, Hunan, China. Mice were given 600 mg/kg D-GalN (Sigma-Aldrich) and 30 ug/kg LPS (Sigma-Aldrich) by intraperitoneal injection. Mice in Sham group were received saline injection. For Fer-1 treatment, mice were received 10 mg/kg Fer-1 at 1 h prior to D-GalN and LPS injection. The wild-type (WT) or HBx-Tg mice were then subjected to D-GalN and LPS administration. For GSK126 treatment, wild-type (WT) or HBx-Tg mice were received GSK126 (150 mg/kg) prior to D-GalN and LPS administration.

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Response regulation HBx facilitates ferroptosis in acute liver failure (ALF) via EZH2/H3K27me3-mediated SLC7A11 suppression.
Diffuse large B-cell lymphoma [ICD-11: 2A81]
 Disease Info 
In total 2 item(s) under this disease
Experiment 1 Reporting the Ferroptosis-centered Disease Response [1]
Target Regulator Histone-lysine N-methyltransferase EZH2 (EZH2) Protein coding
 Regulator Info 
Pathway Response Fatty acid metabolism hsa01212
Ferroptosis hsa04216
Cell Process Cell ferroptosis
Cell proliferation
In Vitro Model
 Karpas-422 cells Diffuse large B-cell lymphoma Homo sapiens CVCL_1325
U-2932 cells Diffuse large B-cell lymphoma Homo sapiens CVCL_1896
WILL-2 cells Diffuse large B-cell lymphoma Homo sapiens CVCL_1901
HEK-293T cells Normal Homo sapiens CVCL_0063
In Vivo Model
All animal experiments were approved by the Institutional Animal Care and Use Committee of Shanghai Institute of Materia Medica and performed in accordance with the Association for Assessment and Accreditation of Laboratory Animal Care. Tumors were measured twice weekly and volumes were calculated using the formula TV=length x width2 x 1/2.

    Click to Show/Hide
Response regulation EZH2 inhibition upregulated-TfR-1 dysregulation leads to drug resistance in EZH2 WT diffuse large B-cell lymphoma (DLBCL). On the other hand, EZH2i impaired the occurrence of ferroptosis by upregulating the heat shock protein family A (Hsp70) member 5 (HSPA5) and stabilizing glutathione peroxidase 4 (GPX4), a ferroptosis suppressor.
Experiment 2 Reporting the Ferroptosis-centered Disease Response [1]
Target Regulator Histone-lysine N-methyltransferase EZH2 (EZH2) Protein coding
 Regulator Info 
Pathway Response Fatty acid metabolism hsa01212
Ferroptosis hsa04216
Cell Process Cell ferroptosis
Cell proliferation
In Vitro Model
 Karpas-422 cells Diffuse large B-cell lymphoma Homo sapiens CVCL_1325
U-2932 cells Diffuse large B-cell lymphoma Homo sapiens CVCL_1896
WILL-2 cells Diffuse large B-cell lymphoma Homo sapiens CVCL_1901
HEK-293T cells Normal Homo sapiens CVCL_0063
In Vivo Model
All animal experiments were approved by the Institutional Animal Care and Use Committee of Shanghai Institute of Materia Medica and performed in accordance with the Association for Assessment and Accreditation of Laboratory Animal Care. Tumors were measured twice weekly and volumes were calculated using the formula TV=length x width2 x 1/2.

    Click to Show/Hide
Response regulation EZH2 inhibition upregulated-TfR-1 dysregulation leads to drug resistance in EZH2 WT diffuse large B-cell lymphoma (DLBCL). On the other hand, EZH2i impaired the occurrence of ferroptosis by upregulating the heat shock protein family A (Hsp70) member 5 (HSPA5) and stabilizing glutathione peroxidase 4 (GPX4), a ferroptosis suppressor.
Oral squamous cell carcinoma [ICD-11: 2B6E]
 Disease Info 
In total 1 item(s) under this disease
Experiment 1 Reporting the Ferroptosis-centered Disease Response [2]
Target Regulator Histone-lysine N-methyltransferase EZH2 (EZH2) Protein coding
 Regulator Info 
Pathway Response Fatty acid metabolism hsa01212
Ferroptosis hsa04216
Cell Process Cell ferroptosis
In Vitro Model
 Tca8113 cells Endocervical adenocarcinoma Homo sapiens CVCL_6851
TSCCA cells Endocervical adenocarcinoma Homo sapiens CVCL_VL15
CAL-27 cells Tongue adenosquamous carcinom Homo sapiens CVCL_1107
SCC-9 cells Tongue squamous cell carcinoma Homo sapiens CVCL_1685
hTECs (Human tongue epithelial cells)
Response regulation EZH2 inhibits the ferroptosis of tongue squamous cell carcinoma cells by inhibiting miR-125b-5p and enhancing SLC7A11. MiR-125b-5p regulates ferroptosis in TSCC cells by targeting SLC7A11.
Multiple sclerosis [ICD-11: 8A40]
 Disease Info 
In total 1 item(s) under this disease
Experiment 1 Reporting the Ferroptosis-centered Disease Response [3]
Target Regulator Histone-lysine N-methyltransferase EZH2 (EZH2) Protein coding
 Regulator Info 
Pathway Response Fatty acid metabolism hsa01212
Ferroptosis hsa04216
Cell Process Cell ferroptosis
In Vitro Model
 hBMSCs (Bone marrow stromal cells)
BV-2 cells Normal Mus musculus CVCL_0182
In Vivo Model
Female C57BL6 mice were randomized into four groups (n = 8/group): the control group (non-EAE mice), the EAE group (EAE mice injected intrathecally with 5 uL PBS when symptoms appeared), the EAE + BMSCs-Exo + mimic negative control (NC) group (EAE mice injected intrathecally with Exos from bone MSCs (BMSCs) transfected with mimic NC [5 uL, 2 ug/L in PBS] when symptoms appeared), and the EAE + BMSCs-Exo + miR-367-3p mimic group (EAE mice injected intrathecally with Exos from BMSCs transfected with miR-367-3p mimic [5 uL, 2 ug/L in PBS] when symptoms appeared).

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Response regulation MiR-367-3p can be delivered by BMSC-Exos into microglia, where miR-367-3p inhibits EZH2 expression and activates the expression of SLC7A11, suppressing microglial ferroptosis and relieving the symptoms of EAE. Experimental autoimmune encephalomyelitis (EAE) is a typical animal model of multiple sclerosis.
Hepatoblastoma [ICD-11: DB91]
 Disease Info 
In total 1 item(s) under this disease
Experiment 1 Reporting the Ferroptosis-centered Disease Response [4]
Target Regulator Histone-lysine N-methyltransferase EZH2 (EZH2) Protein coding
 Regulator Info 
Pathway Response Fatty acid metabolism hsa01212
Ferroptosis hsa04216
Cell Process Cell ferroptosis
In Vitro Model
 hLCs (Liver cells)
mPHs (Mouse primary hepatocytes)
In Vivo Model
Male C57BL/6 mice (n = 20, 6-8-week-old, b.w. 18-23 g) were purchased from SJA Laboratory Animal Co Ltd., Changsha, Hunan, China. Mice were given 600 mg/kg D-GalN (Sigma-Aldrich) and 30 ug/kg LPS (Sigma-Aldrich) by intraperitoneal injection. Mice in Sham group were received saline injection. For Fer-1 treatment, mice were received 10 mg/kg Fer-1 at 1 h prior to D-GalN and LPS injection. The wild-type (WT) or HBx-Tg mice were then subjected to D-GalN and LPS administration. For GSK126 treatment, wild-type (WT) or HBx-Tg mice were received GSK126 (150 mg/kg) prior to D-GalN and LPS administration.

    Click to Show/Hide
Response regulation HBx facilitates ferroptosis in acute liver failure (ALF) via EZH2/H3K27me3-mediated SLC7A11 suppression.
References
Ref 1 Dysregulation of iron homeostasis by TfR-1 renders EZH2 wild type diffuse large B-cell lymphoma resistance to EZH2 inhibition. Acta Pharmacol Sin. 2023 May 25. doi: 10.1038/s41401-023-01097-4. Online ahead of print.
Ref 2 EZH2-mediated SLC7A11 upregulation via miR-125b-5p represses ferroptosis of TSCC. Oral Dis. 2023 Apr;29(3):880-891. doi: 10.1111/odi.14040. Epub 2021 Nov 15.
Ref 3 Mesenchymal stem cell-derived exosomal microRNA-367-3p alleviates experimental autoimmune encephalomyelitis via inhibition of microglial ferroptosis by targeting EZH2. Biomed Pharmacother. 2023 Jun;162:114593. doi: 10.1016/j.biopha.2023.114593. Epub 2023 Mar 29.
Ref 4 HBx facilitates ferroptosis in acute liver failure via EZH2 mediated SLC7A11 suppression. J Biomed Sci. 2021 Oct 6;28(1):67. doi: 10.1186/s12929-021-00762-2.