Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTS922CJ)

• DOT Name: Malignant fibrous histiocytoma-amplified sequence 1 (MFHAS1)
• Synonyms: Malignant fibrous histiocytoma-amplified sequence with leucine-rich tandem repeats 1
• Gene Name: MFHAS1
• Related Disease:
  B-cell neoplasm
  Chronic obstructive pulmonary disease
  Colorectal carcinoma
  Diabetic kidney disease
  Multiple endocrine neoplasia type 1
  Osteoarthritis
  Parkinson disease
  Renal fibrosis
  Systemic lupus erythematosus
  Advanced cancer
  Intellectual disability
  Type-1/2 diabetes
• UniProt ID: MFHA1_HUMAN
• Pfam ID: PF13855
• Sequence:
  MAGMDSGNLKTARLWRDAALRARKLRSNLRQLTLTAAGACPGAGADALESPASPQLVLPA
  NLGDIEALNLGNNGLEEVPEGLGSALGSLRVLVLRRNRFARLPPAVAELGHHLTELDVSH
  NRLTALGAEVVSALRELRKLNLSHNQLPALPAQLGALAHLEELDVSFNRLAHLPDSLSCL
  SRLRTLDVDHNQLTAFPRQLLQLVALEELDVSSNRLRGLPEDISALRALKILWLSGAELG
  TLPAGFCELASLESLMLDNNGLQALPAQFSCLQRLKMLNLSSNLFEEFPAALLPLAGLEE
  LYLSRNQLTSVPSLISGLGRLLTLWLDNNRIRYLPDSIVELTGLEELVLQGNQIAVLPDH
  FGQLSRVGLWKIKDNPLIQPPYEVCMKGIPYIAAYQKELAHSQPAVQPRLKLLLMGHKAA
  GKTLLRHCLTEERVEGCPGGGDKEKCYPPSPPPVSKGIEVTSWTADASRGLRFIVYDLAG
  DESYEVIQPFFLSPGALYVLVVNLATYEPRHFPTTVGSFLHRVGARVPHAVVCIVGTHAD
  LCGERELEEKCLDIHRQIALQEKHDAEGLSRLAKVVDEALARDFELRSASPHAAYYGVSD
  KNLRRRKAHFQYLLNHRLQILSPVLPVSCRDPRHLRRLRDKLLSVAEHREIFPNLHRVLP
  RSWQVLEELHFQPPQAQRLWLSWWDSARLGLQAGLTEDRLQSALSYLHESGKLLYFEDSP
  ALKEHVFHNLTRLIDILNVFFQRDPSLLLHKLLLGTSGEGKAEGESSPPMARSTPSQELL
  RATQLHQYVEGFLLHGLLPAHVIRLLLKPHVQAQQDLQLLLELLEKMGLCYCLNKPKGKP
  LNGSTAWYKFPCYVQNEVPHAEAWINGTNLAGQSFVAEQLQIEYSFPFTFPLGLFARYSV
  QINSHVVHRSDGKFQIFAYRGKVPVVVSYRPARGVLQPDTLSIASHASLPNIWTAWQAIT
  PLVEELNVLLQEWPGLHYTVHILCSKCLKRGSPNPHAFPGELLSQPRPEGVAEIICPKNG
  SERVNVALVYPPTPTVISPCSKKNVGEKHRNQ
• Function: Probable GTP-binding protein. Functions in innate immunity and more specifically the inflammatory response as a regulator of the Toll-like receptor TLR2 and TLR4 signaling pathways. Negatively regulates the part of the TLR4 signaling pathway that leads to the activation of the transcription factor AP-1. By retaining the phosphatase complex PP2A into the cytoplasm, prevents the dephosphorylation of the AP-1 subunit JUN which is required for proper activation of the transcription factor. Both inhibits and activates the TLR2-dependent signaling pathway. Positively regulates the TLR2 signaling pathway to activate specifically the downstream p38 and JNK MAP kinases and promote the polarization of macrophages toward the pro-inflammatory M1 phenotype. It may also play a role in the regulation of inflammation induced by high glucose through the PKB/AKT signaling pathway. Also involved in erythrocyte differentiation through activation of the ERK1/ERK2 signaling pathway.
• Tissue Specificity: Ubiquitously expressed. Overexpressed in malignant fibrous histiocytomas . Expressed in red blood cells (at protein level) .

Molecular Interaction Atlas (MIA) of This DOT

12 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
B-cell neoplasm	DISVY326	Definitive	Biomarker	[1]
Chronic obstructive pulmonary disease	DISQCIRF	Strong	Genetic Variation	[2]
Colorectal carcinoma	DIS5PYL0	Strong	Biomarker	[3]
Diabetic kidney disease	DISJMWEY	Strong	Biomarker	[4]
Multiple endocrine neoplasia type 1	DIS0RJRK	Strong	Genetic Variation	[5]
Osteoarthritis	DIS05URM	Strong	Genetic Variation	[6]
Parkinson disease	DISQVHKL	Strong	Biomarker	[7]
Renal fibrosis	DISMHI3I	Strong	Biomarker	[4]
Systemic lupus erythematosus	DISI1SZ7	Strong	Genetic Variation	[8]
Advanced cancer	DISAT1Z9	Limited	Biomarker	[9]
Intellectual disability	DISMBNXP	Limited	Genetic Variation	[9]
Type-1/2 diabetes	DISIUHAP	Limited	Biomarker	[10]

5 Drug(s) Affected the Post-Translational Modifications of This DOT

Drug Name	Drug ID	Highest Status	Interaction	REF
Valproate	DMCFE9I	Approved	Valproate increases the methylation of Malignant fibrous histiocytoma-amplified sequence 1 (MFHAS1).	[11]
Arsenic	DMTL2Y1	Approved	Arsenic affects the methylation of Malignant fibrous histiocytoma-amplified sequence 1 (MFHAS1).	[16]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene decreases the methylation of Malignant fibrous histiocytoma-amplified sequence 1 (MFHAS1).	[22]
PMID28870136-Compound-52	DMFDERP	Patented	PMID28870136-Compound-52 decreases the phosphorylation of Malignant fibrous histiocytoma-amplified sequence 1 (MFHAS1).	[24]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A increases the methylation of Malignant fibrous histiocytoma-amplified sequence 1 (MFHAS1).	[25]

11 Drug(s) Affected the Gene/Protein Processing of This DOT

Drug Name	Drug ID	Highest Status	Interaction	REF
Ciclosporin	DMAZJFX	Approved	Ciclosporin increases the expression of Malignant fibrous histiocytoma-amplified sequence 1 (MFHAS1).	[12]
Tretinoin	DM49DUI	Approved	Tretinoin decreases the expression of Malignant fibrous histiocytoma-amplified sequence 1 (MFHAS1).	[13]
Acetaminophen	DMUIE76	Approved	Acetaminophen increases the expression of Malignant fibrous histiocytoma-amplified sequence 1 (MFHAS1).	[14]
Estradiol	DMUNTE3	Approved	Estradiol increases the expression of Malignant fibrous histiocytoma-amplified sequence 1 (MFHAS1).	[15]
Quercetin	DM3NC4M	Approved	Quercetin increases the expression of Malignant fibrous histiocytoma-amplified sequence 1 (MFHAS1).	[17]
Vorinostat	DMWMPD4	Approved	Vorinostat decreases the expression of Malignant fibrous histiocytoma-amplified sequence 1 (MFHAS1).	[18]
Triclosan	DMZUR4N	Approved	Triclosan decreases the expression of Malignant fibrous histiocytoma-amplified sequence 1 (MFHAS1).	[19]
Amiodarone	DMUTEX3	Phase 2/3 Trial	Amiodarone increases the expression of Malignant fibrous histiocytoma-amplified sequence 1 (MFHAS1).	[20]
APR-246	DMNFADH	Phase 2	APR-246 affects the expression of Malignant fibrous histiocytoma-amplified sequence 1 (MFHAS1).	[21]
PMID28460551-Compound-2	DM4DOUB	Patented	PMID28460551-Compound-2 increases the expression of Malignant fibrous histiocytoma-amplified sequence 1 (MFHAS1).	[23]
Trichostatin A	DM9C8NX	Investigative	Trichostatin A decreases the expression of Malignant fibrous histiocytoma-amplified sequence 1 (MFHAS1).	[26]

References

• [1] MASL1, a candidate oncogene found in amplification at 8p23.1, is translocated in immunoblastic B-cell lymphoma cell line OCI-LY8.Oncogene. 2004 Apr 1;23(14):2576-81. doi: 10.1038/sj.onc.1207352.
• [2] Genetic landscape of chronic obstructive pulmonary disease identifies heterogeneous cell-type and phenotype associations.Nat Genet. 2019 Mar;51(3):494-505. doi: 10.1038/s41588-018-0342-2. Epub 2019 Feb 25.
• [3] MFHAS1 promotes colorectal cancer progress by regulating polarization of tumor-associated macrophages via STAT6 signaling pathway.Oncotarget. 2016 Nov 29;7(48):78726-78735. doi: 10.18632/oncotarget.12807.
• [4] Malignant fibrous histiocytoma amplified sequence 1 alleviates inflammation and renal fibrosis in diabetic nephropathy by inhibiting TLR4.Biosci Rep. 2019 Nov 29;39(11):BSR20190617. doi: 10.1042/BSR20190617.
• [5] DNA hypermethylation profiles in squamous cell carcinoma of the vulva.Int J Gynecol Pathol. 2009 Jan;28(1):63-75. doi: 10.1097/PGP.0b013e31817d9c61.
• [6] Identification of new susceptibility loci for osteoarthritis (arcOGEN): a genome-wide association study.Lancet. 2012 Sep 1;380(9844):815-23. doi: 10.1016/S0140-6736(12)60681-3. Epub 2012 Jul 3.
• [7] Prediction of the repeat domain structures and impact of parkinsonism-associated variations on structure and function of all functional domains of leucine-rich repeat kinase 2 (LRRK2).Hum Mutat. 2014 Apr;35(4):395-412. doi: 10.1002/humu.22515. Epub 2014 Feb 24.
• [8] Identification of ST3AGL4, MFHAS1, CSNK2A2 and CD226 as loci associated with systemic lupus erythematosus (SLE) and evaluation of SLE genetics in drug repositioning.Ann Rheum Dis. 2018 Jul;77(7):1078-1084. doi: 10.1136/annrheumdis-2018-213093. Epub 2018 Apr 6.
• [9] Homozygous microdeletion of the ERI1 and MFHAS1 genes in a patient with intellectual disability, limb abnormalities, and cardiac malformation.Am J Med Genet A. 2017 Jul;173(7):1955-1960. doi: 10.1002/ajmg.a.38271. Epub 2017 May 9.
• [10] High Glucose Stimulates Expression of MFHAS1 to Mitigate Inflammation via Akt/HO-1 Pathway in Human Umbilical Vein Endothelial Cells.Inflammation. 2018 Mar;41(2):400-408. doi: 10.1007/s10753-017-0696-0.
• [11] Integrative omics data analyses of repeated dose toxicity of valproic acid in vitro reveal new mechanisms of steatosis induction. Toxicology. 2018 Jan 15;393:160-170.
• [12] Comparison of HepG2 and HepaRG by whole-genome gene expression analysis for the purpose of chemical hazard identification. Toxicol Sci. 2010 May;115(1):66-79.
• [13] Transcriptional and Metabolic Dissection of ATRA-Induced Granulocytic Differentiation in NB4 Acute Promyelocytic Leukemia Cells. Cells. 2020 Nov 5;9(11):2423. doi: 10.3390/cells9112423.
• [14] Predictive toxicology using systemic biology and liver microfluidic "on chip" approaches: application to acetaminophen injury. Toxicol Appl Pharmacol. 2012 Mar 15;259(3):270-80.
• [15] 17-Estradiol Activates HSF1 via MAPK Signaling in ER-Positive Breast Cancer Cells. Cancers (Basel). 2019 Oct 11;11(10):1533. doi: 10.3390/cancers11101533.
• [16] Prenatal arsenic exposure and the epigenome: identifying sites of 5-methylcytosine alterations that predict functional changes in gene expression in newborn cord blood and subsequent birth outcomes. Toxicol Sci. 2015 Jan;143(1):97-106. doi: 10.1093/toxsci/kfu210. Epub 2014 Oct 10.
• [17] Comparison of phenotypic and transcriptomic effects of false-positive genotoxins, true genotoxins and non-genotoxins using HepG2 cells. Mutagenesis. 2011 Sep;26(5):593-604.
• [18] Definition of transcriptome-based indices for quantitative characterization of chemically disturbed stem cell development: introduction of the STOP-Toxukn and STOP-Toxukk tests. Arch Toxicol. 2017 Feb;91(2):839-864.
• [19] Transcriptome and DNA methylome dynamics during triclosan-induced cardiomyocyte differentiation toxicity. Stem Cells Int. 2018 Oct 29;2018:8608327.
• [20] Identification by automated screening of a small molecule that selectively eliminates neural stem cells derived from hESCs but not dopamine neurons. PLoS One. 2009 Sep 23;4(9):e7155.
• [21] Mutant p53 reactivation by PRIMA-1MET induces multiple signaling pathways converging on apoptosis. Oncogene. 2010 Mar 4;29(9):1329-38. doi: 10.1038/onc.2009.425. Epub 2009 Nov 30.
• [22] Air pollution and DNA methylation alterations in lung cancer: A systematic and comparative study. Oncotarget. 2017 Jan 3;8(1):1369-1391. doi: 10.18632/oncotarget.13622.
• [23] Cell-based two-dimensional morphological assessment system to predict cancer drug-induced cardiotoxicity using human induced pluripotent stem cell-derived cardiomyocytes. Toxicol Appl Pharmacol. 2019 Nov 15;383:114761. doi: 10.1016/j.taap.2019.114761. Epub 2019 Sep 15.
• [24] Quantitative phosphoproteomics reveal cellular responses from caffeine, coumarin and quercetin in treated HepG2 cells. Toxicol Appl Pharmacol. 2022 Aug 15;449:116110. doi: 10.1016/j.taap.2022.116110. Epub 2022 Jun 7.
• [25] DNA methylome-wide alterations associated with estrogen receptor-dependent effects of bisphenols in breast cancer. Clin Epigenetics. 2019 Oct 10;11(1):138. doi: 10.1186/s13148-019-0725-y.
• [26] A transcriptome-based classifier to identify developmental toxicants by stem cell testing: design, validation and optimization for histone deacetylase inhibitors. Arch Toxicol. 2015 Sep;89(9):1599-618.