Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OT1WUBQX)

• DOT Name: FH1/FH2 domain-containing protein 3 (FHOD3)
• Synonyms: Formactin-2; Formin homolog overexpressed in spleen 2; hFHOS2
• Gene Name: FHOD3
• Related Disease:
  Cardiac disease
  Cardiomyopathy, familial hypertrophic, 28
  Dilated cardiomyopathy 1A
  Drug dependence
  Familial cardiomyopathy
  Glioma
  Narcolepsy
  Substance abuse
  Substance dependence
  High blood pressure
  Hypertrophic cardiomyopathy
  Thyroid cancer
  Thyroid gland carcinoma
  Thyroid tumor
  Type-1 diabetes
• UniProt ID: FHOD3_HUMAN
• Pfam ID: PF02181 ; PF18382
• Sequence:
  MATLACRVQFLDDTDPFNSTNFPEPSRPPLFTFREDLALGTQLAGVHRLLQAPHKLDDCT
  LQLSHNGAYLDLEATLAEQRDELEGFQDDAGRGKKHSIILRTQLSVRVHACIEKLYNSSG
  RDLRRALFSLKQIFQDDKDLVHEFVVAEGLTCLIKVGAEADQNYQNYILRALGQIMLYVD
  GMNGVINRNETIQWLYTLIGSKFRLVVKTALKLLLVFVEYSESNAPLLIQAVTAVDTKRG
  VKPWSNIMEILEEKDGVDTELLVYAMTLVNKTLSGLPDQDTFYDVVDCLEELGIAAVSQR
  HLNKKGTDLDLVEQLNIYEVALRHEDGDETTEPPPSGCRDRRRASVCSSGGGEHRGLDRR
  RSRRHSVQSIKSTLSAPTSPCSQSAPSFKPNQVRDLREKYSNFGNNSYHSSRPSSGSSVP
  TTPTSSVSPPQEARLERSSPSGLLTSSFRQHQESLAAERERRRQEREERLQRIEREERNK
  FRYKYLEQLAAEEHEKELRSRSVSRGRADLSLDLTSPAAPACLAPLSHSPSSSDSQEALT
  VSASSPGTPHHPQASAGDPEPESEAEPEAEAGAGQVADEAGQDIASAHEGAETEVEQALE
  QEPEERASLSEKERQNEGVNERDNCSASSVSSSSSTLEREEKEDKLSRDRTTGLWPAGVQ
  DAGVNGQCGDILTNKRFMLDMLYAHNRKSPDDEEKGDGEAGRTQQEAEAVASLATRISTL
  QANSQTQDESVRRVDVGCLDNRGSVKAFAEKFNSGDLGRGSISPDAEPNDKVPETAPVQP
  KTESDYIWDQLMANPRELRIQDMDFTDLGEEDDIDVLDVDLGHREAPGPPPPPPPTFLGL
  PPPPPPPLLDSIPPPPVPGNLLVPPPPVFNAPQGLGWSQVPRGQPTFTKKKKTIRLFWNE
  VRPFDWPCKNNRRCREFLWSKLEPIKVDTSRLEHLFESKSKELSVSKKTAADGKRQEIIV
  LDSKRSNAINIGLTVLPPPRTIKIAILNFDEYALNKEGIEKILTMIPTDEEKQKIQEAQL
  ANPEIPLGSAEQFLLTLSSISELSARLHLWAFKMDYETTEKEVAEPLLDLKEGIDQLENN
  KTLGFILSTLLAIGNFLNGTNAKAFELSYLEKVPEVKDTVHKQSLLHHVCTMVVENFPDS
  SDLYSEIGAITRSAKVDFDQLQDNLCQMERRCKASWDHLKAIAKHEMKPVLKQRMSEFLK
  DCAERIIILKIVHRRIINRFHSFLLFMGHPPYAIREVNINKFCRIISEFALEYRTTRERV
  LQQKQKRANHRERNKTRGKMITDSGKFSGSSPAPPSQPQGLSYAEDAAEHENMKAVLKTS
  SPSVEDATPALGVRTRSRASRGSTSSWTMGTDDSPNVTDDAADEIMDRIVKSATQVPSQR
  VVPRERKRSRANRKSLRRTLKSGLTPEEARALGLVGTSELQL
• Function: Actin-organizing protein that may cause stress fiber formation together with cell elongation. Isoform 4 may play a role in actin filament polymerization in cardiomyocytes.
• Tissue Specificity: Expressed in the heart, kidney and brain. May be down-regulated in various types of heart diseases, including idiopathic dilated, ventricular dilated, familial dilated and perinatal dilated cardiomyopathies, as well as ischemic heart disease (at protein level).

Molecular Interaction Atlas (MIA) of This DOT

15 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Cardiac disease	DISVO1I5	Strong	Biomarker	[1]
Cardiomyopathy, familial hypertrophic, 28	DISIHJ7B	Strong	Autosomal dominant	[2]
Dilated cardiomyopathy 1A	DIS0RK9Z	Strong	Genetic Variation	[3]
Drug dependence	DIS9IXRC	Strong	Biomarker	[4]
Familial cardiomyopathy	DISBA1TN	Strong	Genetic Variation	[5]
Glioma	DIS5RPEH	Strong	Biomarker	[6]
Narcolepsy	DISLCNLI	Strong	Genetic Variation	[7]
Substance abuse	DIS327VW	Strong	Biomarker	[4]
Substance dependence	DISDRAAR	Strong	Biomarker	[4]
High blood pressure	DISY2OHH	moderate	Altered Expression	[8]
Hypertrophic cardiomyopathy	DISQG2AI	Moderate	Autosomal dominant	[9]
Thyroid cancer	DIS3VLDH	Limited	Genetic Variation	[10]
Thyroid gland carcinoma	DISMNGZ0	Limited	Genetic Variation	[10]
Thyroid tumor	DISLVKMD	Limited	Genetic Variation	[10]
Type-1 diabetes	DIS7HLUB	Limited	Genetic Variation	[11]

2 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 FH1/FH2 domain-containing protein 3 (FHOD3).	[12]
Fulvestrant	DM0YZC6	Approved	Fulvestrant decreases the methylation of FH1/FH2 domain-containing protein 3 (FHOD3).	[22]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Tretinoin	DM49DUI	Approved	Tretinoin decreases the expression of FH1/FH2 domain-containing protein 3 (FHOD3).	[13]
Acetaminophen	DMUIE76	Approved	Acetaminophen decreases the expression of FH1/FH2 domain-containing protein 3 (FHOD3).	[14]
Doxorubicin	DMVP5YE	Approved	Doxorubicin decreases the expression of FH1/FH2 domain-containing protein 3 (FHOD3).	[15]
Cisplatin	DMRHGI9	Approved	Cisplatin decreases the expression of FH1/FH2 domain-containing protein 3 (FHOD3).	[16]
Calcitriol	DM8ZVJ7	Approved	Calcitriol increases the expression of FH1/FH2 domain-containing protein 3 (FHOD3).	[17]
Vorinostat	DMWMPD4	Approved	Vorinostat decreases the expression of FH1/FH2 domain-containing protein 3 (FHOD3).	[18]
Triclosan	DMZUR4N	Approved	Triclosan decreases the expression of FH1/FH2 domain-containing protein 3 (FHOD3).	[19]
Selenium	DM25CGV	Approved	Selenium decreases the expression of FH1/FH2 domain-containing protein 3 (FHOD3).	[20]
Progesterone	DMUY35B	Approved	Progesterone decreases the expression of FH1/FH2 domain-containing protein 3 (FHOD3).	[21]
Panobinostat	DM58WKG	Approved	Panobinostat decreases the expression of FH1/FH2 domain-containing protein 3 (FHOD3).	[18]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene decreases the expression of FH1/FH2 domain-containing protein 3 (FHOD3).	[23]
Leflunomide	DMR8ONJ	Phase 1 Trial	Leflunomide decreases the expression of FH1/FH2 domain-containing protein 3 (FHOD3).	[24]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A decreases the expression of FH1/FH2 domain-containing protein 3 (FHOD3).	[25]
Trichostatin A	DM9C8NX	Investigative	Trichostatin A decreases the expression of FH1/FH2 domain-containing protein 3 (FHOD3).	[26]

References

• [1] RNA-binding proteins RBM20 and PTBP1 regulate the alternative splicing of FHOD3.Int J Biochem Cell Biol. 2019 Jan;106:74-83. doi: 10.1016/j.biocel.2018.11.009. Epub 2018 Nov 20.
• [2] Classification of Genes: Standardized Clinical Validity Assessment of Gene-Disease Associations Aids Diagnostic Exome Analysis and Reclassifications. Hum Mutat. 2017 May;38(5):600-608. doi: 10.1002/humu.23183. Epub 2017 Feb 13.
• [3] Dilated cardiomyopathy-associated FHOD3 variant impairs the ability to induce activation of transcription factor serum response factor.Circ J. 2013;77(12):2990-6. doi: 10.1253/circj.cj-13-0255. Epub 2013 Oct 1.
• [4] Genome wide association for addiction: replicated results and comparisons of two analytic approaches.PLoS One. 2010 Jan 21;5(1):e8832. doi: 10.1371/journal.pone.0008832.
• [5] Exome-wide association study reveals novel susceptibility genes to sporadic dilated cardiomyopathy.PLoS One. 2017 Mar 15;12(3):e0172995. doi: 10.1371/journal.pone.0172995. eCollection 2017.
• [6] Mechanical confinement triggers glioma linear migration dependent on formin FHOD3.Mol Biol Cell. 2016 Apr 15;27(8):1246-61. doi: 10.1091/mbc.E15-08-0565. Epub 2016 Feb 24.
• [7] Genome-wide association database developed in the Japanese Integrated Database Project.J Hum Genet. 2009 Sep;54(9):543-6. doi: 10.1038/jhg.2009.68. Epub 2009 Jul 24.
• [8] The actin-organizing formin protein Fhod3 is required for postnatal development and functional maintenance of the adult heart in mice.J Biol Chem. 2018 Jan 5;293(1):148-162. doi: 10.1074/jbc.M117.813931. Epub 2017 Nov 20.
• [9] Formin Homology 2 Domain Containing 3 (FHOD3) Is a Genetic Basis for Hypertrophic Cardiomyopathy. J Am Coll Cardiol. 2018 Nov 13;72(20):2457-2467. doi: 10.1016/j.jacc.2018.10.001.
• [10] An integrated analysis of cancer genes in thyroid cancer.Oncol Rep. 2016 Feb;35(2):962-70. doi: 10.3892/or.2015.4466. Epub 2015 Dec 1.
• [11] Follow-up of 1715 SNPs from the Wellcome Trust Case Control Consortium genome-wide association study in type I diabetes families.Genes Immun. 2009 Dec;10 Suppl 1(Suppl 1):S85-94. doi: 10.1038/gene.2009.97.
• [12] 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.
• [13] Development of a neural teratogenicity test based on human embryonic stem cells: response to retinoic acid exposure. Toxicol Sci. 2011 Dec;124(2):370-7.
• [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] Bringing in vitro analysis closer to in vivo: studying doxorubicin toxicity and associated mechanisms in 3D human microtissues with PBPK-based dose modelling. Toxicol Lett. 2018 Sep 15;294:184-192.
• [16] The thioxotriazole copper(II) complex A0 induces endoplasmic reticulum stress and paraptotic death in human cancer cells. J Biol Chem. 2009 Sep 4;284(36):24306-19.
• [17] Large-scale in silico and microarray-based identification of direct 1,25-dihydroxyvitamin D3 target genes. Mol Endocrinol. 2005 Nov;19(11):2685-95.
• [18] 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.
• [19] Transcriptome and DNA methylome dynamics during triclosan-induced cardiomyocyte differentiation toxicity. Stem Cells Int. 2018 Oct 29;2018:8608327.
• [20] Selenium and vitamin E: cell type- and intervention-specific tissue effects in prostate cancer. J Natl Cancer Inst. 2009 Mar 4;101(5):306-20.
• [21] Unique transcriptome, pathways, and networks in the human endometrial fibroblast response to progesterone in endometriosis. Biol Reprod. 2011 Apr;84(4):801-15.
• [22] 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.
• [23] Identification of a transcriptomic signature of food-relevant genotoxins in human HepaRG hepatocarcinoma cells. Food Chem Toxicol. 2020 Jun;140:111297. doi: 10.1016/j.fct.2020.111297. Epub 2020 Mar 28.
• [24] Endoplasmic reticulum stress and MAPK signaling pathway activation underlie leflunomide-induced toxicity in HepG2 Cells. Toxicology. 2017 Dec 1;392:11-21.
• [25] Bisphenol A induces DSB-ATM-p53 signaling leading to cell cycle arrest, senescence, autophagy, stress response, and estrogen release in human fetal lung fibroblasts. Arch Toxicol. 2018 Apr;92(4):1453-1469.
• [26] From transient transcriptome responses to disturbed neurodevelopment: role of histone acetylation and methylation as epigenetic switch between reversible and irreversible drug effects. Arch Toxicol. 2014 Jul;88(7):1451-68.