Details of Host Protein-DME Interaction (HOSPPI)

General Information of Drug-Metabolizing Enzyme (DME ID: DME0002)
DME Name	Aromatase (CYP19A1), Homo sapiens	DME Info
UniProt ID	CP19A_HUMAN
EC Number	EC: 1.14.14.14 (Click to Show/Hide the Complete EC Tree) Oxidoreductase Oxygen paired donor oxidoreductase Flavin/flavoprotein donor oxidoreductase EC: 1.14.14.14
Lineage	Species: Homo sapiens (Click to Show/Hide the Complete Species Lineage) Kingdom: Metazoa Phylum: Chordata Class: Mammalia Order: Primates Family: Hominidae Genus: Homo Species: Homo sapiens
Interactome

Disease Specific Interactions between Host Protein and DME (HOSPPI)
ICD Disease Classification Healthy
ICD-11: Healthy		Click to Show/Hide the Full List of HOSPPI: 8 HOSPPI
Oligomerization
Mutated NADPH-CYP450 reductase (mPOR)		Health		Heterooligomer
Uniprot ID	NCPR_HUMAN
Interaction Name	mPOR-CYP19A1 heterooligomerization				[2]
Studied Cell Lines	Escherichia coli BL21(DE3) cell line
Description	Mutated NADPH-CYP450 reductase (mPOR) is reported to heterooligomerize with the CYP19A1 protein, which leads to a suppressed activity of the drug-metabolizing enzyme Aromatase. As a result, the interaction between mPOR and CYP19A1 can inhibit the drug-metabolizing process of Aromatase.
NADPH-CYP450 reductase (POR)		Health		Heterodimer
Uniprot ID	NCPR_HUMAN
Interaction Name	POR-CYP19A1 heterodimerization				[3]
Studied Cell Lines	Human embryonic kidney cell line (HEK293)
Description	NADPH-CYP450 reductase (POR) is reported to heterodimerize with the CYP19A1 protein, which leads to activation of the drug-metabolizing enzyme Aromatase. As a result, the interaction between POR and CYP19A1 can activate the drug-metabolizing process of Aromatase.
Steroid 21-hydroxylase (CYP21A2)		Health		Heterooligomer
Uniprot ID	CP21A_HUMAN
Interaction Name	CYP21A2-CYP19A1 heterooligomerization				[6]
Studied Cell Lines	Escherichia coli JM109 competent cell line
Affected Substrate(s):	pregnenolone
Description	Steroid 21-hydroxylase (CYP21A2) is reported to heterooligomerize with the CYP19A1 protein, which leads to a decreased activity of the drug-metabolizing enzyme Aromatase. As a result, the interaction between CYP21A2 and CYP19A1 can decrease the drug-metabolizing process of Aromatase.
Transcription-factor regulation
Nuclear receptor family 0 B1 (NR0B1)		Health		Repression
Uniprot ID	NR0B1_HUMAN
Interaction Name	NR0B1-CYP19A1 interaction				[4], [5]
Studied Cell Lines	Human endometriotic and endometrial stromal cell lines
Ensembl ID	ENSG00000169297
Description	Nuclear receptor family 0 B1 (NR0B1) is reported to repress the transcription of CYP19A1 gene, which leads to a decreased expression of the drug-metabolizing enzyme Aromatase. As a result, the interaction between NR0B1 and CYP19A1 can repress the drug-metabolizing process of Aromatase.
Steroidogenic factor 1 (NR5A1)		Health		Activation
Uniprot ID	STF1_HUMAN
Interaction Name	NR5A1-CYP19A1 interaction				[4], [7]
Studied Cell Lines	Human endometriotic and endometrial stromal cell lines
Ensembl ID	ENSG00000136931
Description	Steroidogenic factor 1 (NR5A1) is reported to activate the transcription of CYP19A1 gene, which leads to an increased expression of the drug-metabolizing enzyme Aromatase. As a result, the interaction between NR5A1 and CYP19A1 can activate the drug-metabolizing process of Aromatase.
Upstream stimulatory 1 (USF1)		Health		Repression
Uniprot ID	USF1_HUMAN
Interaction Name	USF1-CYP19A1 interaction				[8]
Studied Cell Lines	Human trophoblast cell line
Ensembl ID	ENSG00000158773
Description	Upstream stimulatory 1 (USF1) is reported to repress the transcription of CYP19A1 gene, which leads to a decreased expression of the drug-metabolizing enzyme Aromatase. As a result, the interaction between USF1 and CYP19A1 can repress the drug-metabolizing process of Aromatase.
Upstream stimulatory 2 (USF2)		Health		Repression
Uniprot ID	USF2_HUMAN
Interaction Name	USF2-CYP19A1 interaction				[8]
Studied Cell Lines	Human trophoblast cell line
Ensembl ID	ENSG00000105698
Description	Upstream stimulatory 2 (USF2) is reported to repress the transcription of CYP19A1 gene, which leads to a decreased expression of the drug-metabolizing enzyme Aromatase. As a result, the interaction between USF2 and CYP19A1 can repress the drug-metabolizing process of Aromatase.
Non-coding RNA regulation
hsa-miR-378a-3p		Health		Suppression
miRBase ID	MIMAT0000732
Interaction Name	hsa-miR-378a-3p--CYP19A1 regulation				[1]
Studied Cell Lines	Granulosa cells
Description	hsa-miR-378a-3p is reported to suppress CYP19A1 mRNA translation by binding to the 3' untranslated region (3'UTR) of CYP19A1 mRNA, which leads to a decreased expression of the drug-metabolizing enzyme Aromatase.
ICD Disease Classification 02 Neoplasms
ICD-11: 2A00 Brain cancer		Click to Show/Hide the Full List of HOSPPI: 1 HOSPPI
DNA methylation
DNA methyltransferase (DNMT)		Brain neuroblastoma		Moderate hypomethylation
Interaction Name	DNMT-CYP19A1 interaction
The Methylation Level of Disease Section Compare with the Healthy Individual Tissue	Moderate hypomethylation p-value: 1.71E-06; delta-beta: -2.04E-01
Description	DNA methyltransferase (DNMT) is reported to moderatly hypo-methylate the CYP19A1 gene, which leads to a moderatly increased expression of the drug-metabolizing enzyme Aromatase. As a result, the interaction between DNMT and CYP19A1 can moderatly affect the drug-metabolizing process of Aromatase.
DME methylation in the diseased tissue of patients DME methylation in the normal tissue of healthy individuals
Violin Diagram of DME Disease-specific Methylation Level			Click to View the Clearer Original Diagram
Download DME methylation barchart for all samples Download DME methylation data of patients in the disease section of the tissue Download DME methylation data in the tissue of healthy individual
ICD-11: 2B30 Lymphoma		Click to Show/Hide the Full List of HOSPPI: 1 HOSPPI
DNA methylation
DNA methyltransferase (DNMT)		Lymphoma		Moderate hypomethylation
Interaction Name	DNMT-CYP19A1 interaction
The Methylation Level of Disease Section Compare with the Healthy Individual Tissue	Moderate hypomethylation p-value: 1.15E-06; delta-beta: -2.09E-01
Description	DNA methyltransferase (DNMT) is reported to moderatly hypo-methylate the CYP19A1 gene, which leads to a moderatly increased expression of the drug-metabolizing enzyme Aromatase. As a result, the interaction between DNMT and CYP19A1 can moderatly affect the drug-metabolizing process of Aromatase.
DME methylation in the diseased tissue of patients DME methylation in the normal tissue of healthy individuals
Violin Diagram of DME Disease-specific Methylation Level			Click to View the Clearer Original Diagram
Download DME methylation barchart for all samples Download DME methylation data of patients in the disease section of the tissue Download DME methylation data in the tissue of healthy individual
ICD-11: 2C60 Breast cancer		Click to Show/Hide the Full List of HOSPPI: 7 HOSPPI
Oligomerization
Progesterone receptor 1 (PGRMC1)		Breast cancer		Heterooligomer
Uniprot ID	PGRC1_HUMAN
Interaction Name	PGRMC1-CYP19A1 heterooligomerization				[16]
Studied Cell Lines	Breast carcinoma cell line (MCF7)
Affected Substrate(s):	Androst-4-ene-3,17-dione (Metabolic product: Androst-4-ene-3,17-dione conversion)
Description	Progesterone receptor 1 (PGRMC1) is reported to heterooligomerize with the CYP19A1 protein, which leads to activation of the drug-metabolizing enzyme Aromatase. As a result, the interaction between PGRMC1 and CYP19A1 can activate the drug-metabolizing process of Aromatase.
Transcription-factor regulation
AMP element-binding 1 (CREB1)		Breast cancer		Activation
Uniprot ID	CREB1_HUMAN
Interaction Name	CREB1-CYP19A1 interaction				[9], [10]
Studied Cell Lines	MCF-7 and MDA-MB-231 cell lines
Ensembl ID	ENSG00000118260
Description	AMP element-binding 1 (CREB1) is reported to activate the transcription of CYP19A1 gene, which leads to an increased expression of the drug-metabolizing enzyme Aromatase. As a result, the interaction between CREB1 and CYP19A1 can activate the drug-metabolizing process of Aromatase.
Estrogen receptor (ESR1)		Breast cancer		Activation
Uniprot ID	ESR1_HUMAN
Interaction Name	ESR1-CYP19A1 interaction				[11]
Studied Cell Lines	SK-BR-3 and MCF-7 cell lines
Ensembl ID	ENSG00000091831
Description	Estrogen receptor (ESR1) is reported to activate the transcription of CYP19A1 gene, which leads to an increased expression of the drug-metabolizing enzyme Aromatase. As a result, the interaction between ESR1 and CYP19A1 can activate the drug-metabolizing process of Aromatase.
Estrogen receptor-like 1 (ESRRA)		Breast cancer		Activation
Uniprot ID	ERR1_HUMAN
Interaction Name	ESRRA-CYP19A1 interaction				[10], [12], [13]
Studied Cell Lines	MCF-7 and MDA-MB-231 cell lines
Ensembl ID	ENSG00000173153
Description	Estrogen receptor-like 1 (ESRRA) is reported to activate the transcription of CYP19A1 gene, which leads to an increased expression of the drug-metabolizing enzyme Aromatase. As a result, the interaction between ESRRA and CYP19A1 can activate the drug-metabolizing process of Aromatase.
Glucocorticoid receptor (NR3C1)		Breast cancer		Activation
Uniprot ID	GCR_HUMAN
Interaction Name	NR3C1-CYP19A1 interaction				[9]
Studied Cell Lines	MCF-7 cell line
Ensembl ID	ENSG00000113580
Description	Glucocorticoid receptor (NR3C1) is reported to activate the transcription of CYP19A1 gene, which leads to an increased expression of the drug-metabolizing enzyme Aromatase. As a result, the interaction between NR3C1 and CYP19A1 can activate the drug-metabolizing process of Aromatase.
Progesterone receptor (PGR)		Breast cancer		Repression
Uniprot ID	PRGR_HUMAN
Interaction Name	PGR-CYP19A1 interaction				[15]
Studied Cell Lines	T47D and MCF-7 cell lines
Ensembl ID	ENSG00000082175
Description	Progesterone receptor (PGR) is reported to repress the transcription of CYP19A1 gene, which leads to a decreased expression of the drug-metabolizing enzyme Aromatase. As a result, the interaction between PGR and CYP19A1 can repress the drug-metabolizing process of Aromatase.
Non-coding RNA regulation
hsa-let-7f-5p		Breast cancer		Suppression
miRBase ID	MIMAT0000067
Interaction Name	hsa-let-7f-5p--CYP19A1 regulation				[14]
Studied Cell Lines	MCF-7 and SK-BR-3 cell lines
Description	hsa-let-7f-5p is reported to suppress CYP19A1 mRNA translation by binding to the 3' untranslated region (3'UTR) of CYP19A1 mRNA, which leads to a decreased expression of the drug-metabolizing enzyme Aromatase.
ICD-11: 2C73 Ovarian cancer		Click to Show/Hide the Full List of HOSPPI: 3 HOSPPI
Transcription-factor regulation
Nuclear factor kappa-B p105 (NFKB1)		Ovarian cancer		Repression
Uniprot ID	NFKB1_HUMAN
Interaction Name	NFKB1-CYP19A1 interaction				[17]
Studied Cell Lines	KGN cell line
Ensembl ID	ENSG00000109320
Description	Nuclear factor kappa-B p105 (NFKB1) is reported to repress the transcription of CYP19A1 gene, which leads to a decreased expression of the drug-metabolizing enzyme Aromatase. As a result, the interaction between NFKB1 and CYP19A1 can repress the drug-metabolizing process of Aromatase.
RING finger protein 53 (BRCA1)		Ovarian cancer		Activation
Uniprot ID	BRCA1_HUMAN
Interaction Name	BRCA1-CYP19A1 interaction				[7]
Studied Cell Lines	KGN cell line
Description	RING finger protein 53 (BRCA1) is reported to activate the transcription of CYP19A1 gene, which leads to an increased expression of the drug-metabolizing enzyme Aromatase. As a result, the interaction between BRCA1 and CYP19A1 can activate the drug-metabolizing process of Aromatase.
Transcription factor p65 (RELA)		Ovarian cancer		Repression
Uniprot ID	TF65_HUMAN
Interaction Name	RELA-CYP19A1 interaction				[17], [18]
Studied Cell Lines	KGN cell line
Ensembl ID	ENSG00000173039
Description	Transcription factor p65 (RELA) is reported to repress the transcription of CYP19A1 gene, which leads to a decreased expression of the drug-metabolizing enzyme Aromatase. As a result, the interaction between RELA and CYP19A1 can repress the drug-metabolizing process of Aromatase.
ICD-11: 2C75 Placenta cancer		Click to Show/Hide the Full List of HOSPPI: 2 HOSPPI
Non-coding RNA regulation
hsa-miR-106a-5p		Choriocarcinoma		Suppression
miRBase ID	MIMAT0000103
Interaction Name	hsa-miR-106a-5p--CYP19A1 regulation				[19]
Studied Cell Lines	Human choriocarcinoma JEG-3 cell line
Description	hsa-miR-106a-5p is reported to suppress CYP19A1 mRNA translation by binding to the 3' untranslated region (3'UTR) of CYP19A1 mRNA, which leads to a decreased expression of the drug-metabolizing enzyme Aromatase.
hsa-miR-19b-3p		Choriocarcinoma		Suppression
miRBase ID	MIMAT0000074
Interaction Name	hsa-miR-19b-3p--CYP19A1 regulation				[19]
Studied Cell Lines	Human choriocarcinoma JEG-3 cell line
Description	hsa-miR-19b-3p is reported to suppress CYP19A1 mRNA translation by binding to the 3' untranslated region (3'UTR) of CYP19A1 mRNA, which leads to a decreased expression of the drug-metabolizing enzyme Aromatase.
ICD-11: 2D11 Adrenocortical carcinoma		Click to Show/Hide the Full List of HOSPPI: 2 HOSPPI
Transcription-factor regulation
Steroidogenic factor 1 (NR5A1)		Adrenocortical carcinoma		Repression
Uniprot ID	STF1_HUMAN
Interaction Name	NR5A1-CYP19A1 interaction				[5]
Studied Cell Lines	Adrenocortical carcinoma cell line
Ensembl ID	ENSG00000136931
Description	Steroidogenic factor 1 (NR5A1) is reported to repress the transcription of CYP19A1 gene, which leads to a decreased expression of the drug-metabolizing enzyme Aromatase. As a result, the interaction between NR5A1 and CYP19A1 can repress the drug-metabolizing process of Aromatase.
Non-coding RNA regulation
hsa-miR-98-5p		Adrenocortical carcinoma		Suppression
miRBase ID	MIMAT0000096
Interaction Name	hsa-miR-98-5p--CYP19A1 regulation				[20]
Studied Cell Lines	H295R cell line
Description	hsa-miR-98-5p is reported to suppress CYP19A1 mRNA translation by binding to the 3' untranslated region (3'UTR) of CYP19A1 mRNA, which leads to a decreased expression of the drug-metabolizing enzyme Aromatase.
ICD-11: 2F32 Benign ovarian neoplasm		Click to Show/Hide the Full List of HOSPPI: 1 HOSPPI
Transcription-factor regulation
Transcription factor AP-1 (JUN)		Virilizing Brenner Tumor		Repression
Uniprot ID	JUN_HUMAN
Interaction Name	JUN-CYP19A1 interaction				[21]
Studied Cell Lines	Fibrothecoma-like and luteinized stromal cell line
Ensembl ID	ENSG00000177606
Description	Transcription factor AP-1 (JUN) is reported to repress the transcription of CYP19A1 gene, which leads to a decreased expression of the drug-metabolizing enzyme Aromatase. As a result, the interaction between JUN and CYP19A1 can repress the drug-metabolizing process of Aromatase.
ICD Disease Classification 16 Genitourinary system diseases
ICD-11: GA10 Endometriosis		Click to Show/Hide the Full List of HOSPPI: 3 HOSPPI
Transcription-factor regulation
Liver activator protein (LAP)		Endometriosis		Repression
Uniprot ID	CEBPB_HUMAN
Interaction Name	LAP-CYP19A1 interaction				[22]
Studied Cell Lines	Human endometriotic stromal cell line
Ensembl ID	ENSG00000172216
Description	Liver activator protein (LAP) is reported to repress the transcription of CYP19A1 gene, which leads to a decreased expression of the drug-metabolizing enzyme Aromatase. As a result, the interaction between LAP and CYP19A1 can repress the drug-metabolizing process of Aromatase.
Nuclear factor NF-IL6-beta (CEBPD)		Endometriosis		Repression
Uniprot ID	CEBPD_HUMAN
Interaction Name	CEBPD-CYP19A1 interaction				[22]
Studied Cell Lines	Human endometriotic stromal cell line
Ensembl ID	ENSG00000221869
Description	Nuclear factor NF-IL6-beta (CEBPD) is reported to repress the transcription of CYP19A1 gene, which leads to a decreased expression of the drug-metabolizing enzyme Aromatase. As a result, the interaction between CEBPD and CYP19A1 can repress the drug-metabolizing process of Aromatase.
Wilms tumor protein (WT1)		Endometriosis		Repression
Uniprot ID	WT1_HUMAN
Interaction Name	WT1-CYP19A1 interaction				[4]
Studied Cell Lines	Human endometriotic stromal cell line
Ensembl ID	ENSG00000184937
Description	Wilms tumor protein (WT1) is reported to repress the transcription of CYP19A1 gene, which leads to a decreased expression of the drug-metabolizing enzyme Aromatase. As a result, the interaction between WT1 and CYP19A1 can repress the drug-metabolizing process of Aromatase.
ICD-11: GA30 Menopausal disorder		Click to Show/Hide the Full List of HOSPPI: 1 HOSPPI
Transcription-factor regulation
Forkhead box protein L2 (FOXL2)		Menopausal disorder		Repression
Uniprot ID	FOXL2_HUMAN
Interaction Name	FOXL2-CYP19A1 interaction				[23]
Studied Cell Lines	CHO cell line
Ensembl ID	ENSG00000183770
Description	Forkhead box protein L2 (FOXL2) is reported to repress the transcription of CYP19A1 gene, which leads to a decreased expression of the drug-metabolizing enzyme Aromatase. As a result, the interaction between FOXL2 and CYP19A1 can repress the drug-metabolizing process of Aromatase.
ICD Disease Classification 18 Pregnancy/childbirth/the puerperium
ICD-11: JA24 Preeclampsia		Click to Show/Hide the Full List of HOSPPI: 1 HOSPPI
Non-coding RNA regulation
hsa-miR-515-5p		Preeclampsia		Suppression
miRBase ID	MIMAT0002826
Interaction Name	hsa-miR-515-5p--CYP19A1 regulation				[24]
Studied Cell Lines	Preeclampsia cells
Description	hsa-miR-515-5p is reported to suppress CYP19A1 mRNA translation by binding to the 3' untranslated region (3'UTR) of CYP19A1 mRNA, which leads to a decreased expression of the drug-metabolizing enzyme Aromatase.

References
1	Micro-RNA378 (miR-378) regulates ovarian estradiol production by targeting aromatase. Endocrinology. 2011 Oct;152(10):3941-51.
2	Variability in loss of multiple enzyme activities due to the human genetic variation P284T located in the flexible hinge region of NADPH cytochrome P450 oxidoreductase. Front Pharmacol. 2019 Oct 15;10:1187.
3	Organization of cytochrome P450 enzymes involved in sex steroid synthesis: protein-protein interactions in lipid membranes. J Biol Chem. 2009 Nov 27;284(48):33224-32.
4	WT1 and DAX-1 inhibit aromatase P450 expression in human endometrial and endometriotic stromal cells. J Clin Endocrinol Metab. 2002 Sep;87(9):4369-77.
5	Knockdown of SF-1 and RNF31 affects components of steroidogenesis, TGFbeta, and Wnt/beta-catenin signaling in adrenocortical carcinoma cells. PLoS One. 2012;7(3):e32080.
6	Mechanism of intermolecular interactions of microsomal cytochrome P450s CYP17 and CYP21 involved in steroid hormone biosynthesis. Biochemistry (Mosc). 2012 Jun;77(6):585-92.
7	BRCA1/BARD1 complex interacts with steroidogenic factor 1--A potential mechanism for regulation of aromatase expression by BRCA1. J Steroid Biochem Mol Biol. 2011 Jan;123(1-2):71-8.
8	USF1 and USF2 mediate inhibition of human trophoblast differentiation and CYP19 gene expression by Mash-2 and hypoxia. Mol Cell Biol. 2003 Sep;23(17):6117-28.
9	Grape seed extract is an aromatase inhibitor and a suppressor of aromatase expression. Cancer Res. 2006 Jun 1;66(11):5960-7.
10	Positive and negative transcriptional regulation of aromatase expression in human breast cancer tissue. J Steroid Biochem Mol Biol. 2005 May;95(1-5):17-23.
11	Induction of aromatase (CYP19) expression in breast cancer cells through a nongenomic action of estrogen receptor alpha. Cancer Res. 2003 Jul 1;63(13):3546-55.
12	Estrogen receptor-related receptor alpha mediates up-regulation of aromatase expression by prostaglandin E2 in prostate stromal cells. Mol Endocrinol. 2010 Jun;24(6):1175-86.
13	SIRT1 positively regulates breast cancer associated human aromatase (CYP19A1) expression. Mol Endocrinol. 2013 Mar;27(3):480-90.
14	Aromatase inhibitor treatment of breast cancer cells increases the expression of let-7f, a microRNA targeting CYP19A1. J Pathol. 2012 Jul;227(3):357-66.
15	Progesterone receptor inhibits aromatase and inflammatory response pathways in breast cancer cells via ligand-dependent and ligand-independent mechanisms. Mol Endocrinol. 2008 Aug;22(8):1812-24.
16	S2R(Pgrmc1): the cytochrome-related sigma-2 receptor that regulates lipid and drug metabolism and hormone signaling. Expert Opin Drug Metab Toxicol. 2012 Mar;8(3):361-70.
17	Activation of peroxisome proliferator-activated receptor-gamma and retinoid X receptor inhibits aromatase transcription via nuclear factor-kappaB. Endocrinology. 2005 Jan;146(1):85-92.
18	CCAAT/enhancer binding protein delta up-regulates aromatase promoters I.3/II in breast cancer epithelial cells. Cancer Res. 2008 Jun 1;68(11):4455-64.
19	The c-Myc-regulated microRNA-17~92 (miR-17~92) and miR-106a~363 clusters target hCYP19A1 and hGCM1 to inhibit human trophoblast differentiation. Mol Cell Biol. 2013 May;33(9):1782-96.
20	Evidence for microRNA-mediated regulation of steroidogenesis by hypoxia. Environ Sci Technol. 2015 Jan 20;49(2):1138-47.
21	A case of virilizing brenner tumor in a postmenopausal woman with stromal androgenic activity. Int J Gynecol Pathol. 2006 Jul;25(3):230-2.
22	Regulation of aromatase P450 expression in endometriotic and endometrial stromal cells by CCAAT/enhancer binding proteins (C/EBPs): decreased C/EBPbeta in endometriosis is associated with overexpression of aromatase. J Clin Endocrinol Metab. 2002 May;87(5):2336-45.
23	Mutant Forkhead L2 (FOXL2) proteins associated with premature ovarian failure (POF) dimerize with wild-type FOXL2, leading to altered regulation of genes associated with granulosa cell differentiation. Endocrinology. 2011 Oct;152(10):3917-29.
24	Primate-specific miR-515 family members inhibit key genes in human trophoblast differentiation and are upregulated in preeclampsia. Proc Natl Acad Sci U S A. 2016 Nov 8;113(45):E7069-E7076.

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