Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTPOT23F)

• DOT Name: Protein diaphanous homolog 3 (DIAPH3)
• Synonyms: Diaphanous-related formin-3; DRF3; MDia2
• Gene Name: DIAPH3
• Related Disease:
  Autism
  Epithelial neoplasm
  Epithelial ovarian cancer
  Lung adenocarcinoma
  Lung cancer
  Lung carcinoma
  Metastatic prostate carcinoma
  Neoplasm
  Prostate neoplasm
  Triple negative breast cancer
  Autosomal dominant auditory neuropathy 1
  Hearing loss, autosomal recessive
  Laryngeal squamous cell carcinoma
  Prostate carcinoma
  Autosomal dominant nonsyndromic hearing loss
  Acute myelogenous leukaemia
  Adult glioblastoma
  Auditory neuropathy
  Breast cancer
  Breast carcinoma
  Glioblastoma multiforme
  Hepatocellular carcinoma
  Prostate cancer
• UniProt ID: DIAP3_HUMAN
• PDB ID: 5UWP; 6X2Y
• Pfam ID: PF06367 ; PF06371 ; PF02181
• Sequence:
  MERHQPRLHHPAQGSAAGTPYPSSASLRGCRESKMPRRKGPQHPPPPSGPEEPGEKRPKF
  HLNIRTLTDDMLDKFASIRIPGSKKERPPLPNLKTAFASSDCSAAPLEMMENFPKPLSEN
  ELLELFEKMMEDMNLNEDKKAPLREKDFSIKKEMVMQYINTASKTGSLKRSRQISPQEFI
  HELKMGSADERLVTCLESLRVSLTSNPVSWVESFGHEGLGLLLDILEKLISGKIQEKVVK
  KNQHKVIQCLKALMNTQYGLERIMSEERSLSLLAKAVDPRHPNMMTDVVKLLSAVCIVGE
  ESILEEVLEALTSAGEEKKIDRFFCIVEGLRHNSVQLQVACMQLINALVTSPDDLDFRLH
  IRNEFMRCGLKEILPNLKCIKNDGLDIQLKVFDEHKEEDLFELSHRLEDIRAELDEAYDV
  YNMVWSTVKETRAEGYFISILQHLLLIRNDYFIRQQYFKLIDECVSQIVLHRDGMDPDFT
  YRKRLDLDLTQFVDICIDQAKLEEFEEKASELYKKFEKEFTDHQETQAELQKKEAKINEL
  QAELQAFKSQFGALPADCNIPLPPSKEGGTGHSALPPPPPLPSGGGVPPPPPPPPPPPLP
  GMRMPFSGPVPPPPPLGFLGGQNSPPLPILPFGLKPKKEFKPEISMRRLNWLKIRPHEMT
  ENCFWIKVNENKYENVDLLCKLENTFCCQQKERREEEDIEEKKSIKKKIKELKFLDSKIA
  QNLSIFLSSFRVPYEEIRMMILEVDETRLAESMIQNLIKHLPDQEQLNSLSQFKSEYSNL
  CEPEQFVVVMSNVKRLRPRLSAILFKLQFEEQVNNIKPDIMAVSTACEEIKKSKSFSKLL
  ELVLLMGNYMNAGSRNAQTFGFNLSSLCKLKDTKSADQKTTLLHFLVEICEEKYPDILNF
  VDDLEPLDKASKVSVETLEKNLRQMGRQLQQLEKELETFPPPEDLHDKFVTKMSRFVISA
  KEQYETLSKLHENMEKLYQSIIGYYAIDVKKVSVEDFLTDLNNFRTTFMQAIKENIKKRE
  AEEKEKRVRIAKELAERERLERQQKKKRLLEMKTEGDETGVMDNLLEALQSGAAFRDRRK
  RTPMPKDVRQSLSPMSQRPVLKVCNHENQKVQLTEGSRSHYNINCNSTRTPVAKELNYNL
  DTHTSTGRIKAAEKKEACNVESNRKKETELLGSFSKNESVPEVEALLARLRAL
• Function: Actin nucleation and elongation factor required for the assembly of F-actin structures, such as actin cables and stress fibers. Required for cytokinesis, stress fiber formation and transcriptional activation of the serum response factor. Binds to GTP-bound form of Rho and to profilin: acts in a Rho-dependent manner to recruit profilin to the membrane, where it promotes actin polymerization. DFR proteins couple Rho and Src tyrosine kinase during signaling and the regulation of actin dynamics. Also acts as an actin nucleation and elongation factor in the nucleus by promoting nuclear actin polymerization inside the nucleus to drive serum-dependent SRF-MRTFA activity.
• KEGG Pathway:
  Regulation of actin cytoskeleton (hsa04810)
  Cytoskeleton in muscle cells (hsa04820)
• Reactome Pathway:
  RHOA GTPase cycle (R-HSA-8980692)
  RHOB GTPase cycle (R-HSA-9013026)
  RHOC GTPase cycle (R-HSA-9013106)
  CDC42 GTPase cycle (R-HSA-9013148)
  RAC1 GTPase cycle (R-HSA-9013149)
  RAC2 GTPase cycle (R-HSA-9013404)
  RHOD GTPase cycle (R-HSA-9013405)
  RHOQ GTPase cycle (R-HSA-9013406)
  RHOG GTPase cycle (R-HSA-9013408)
  RHOJ GTPase cycle (R-HSA-9013409)
  RAC3 GTPase cycle (R-HSA-9013423)
  RHOF GTPase cycle (R-HSA-9035034)
  RHO GTPases Activate Formins (R-HSA-5663220)

Molecular Interaction Atlas (MIA) of This DOT

23 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Autism	DISV4V1Z	Strong	Biomarker	[1]
Epithelial neoplasm	DIS0T594	Strong	Biomarker	[2]
Epithelial ovarian cancer	DIS56MH2	Strong	Biomarker	[2]
Lung adenocarcinoma	DISD51WR	Strong	Altered Expression	[3]
Lung cancer	DISCM4YA	Strong	Biomarker	[3]
Lung carcinoma	DISTR26C	Strong	Biomarker	[3]
Metastatic prostate carcinoma	DISVBEZ9	Strong	Biomarker	[4]
Neoplasm	DISZKGEW	Strong	Biomarker	[4]
Prostate neoplasm	DISHDKGQ	Strong	Genetic Variation	[5]
Triple negative breast cancer	DISAMG6N	Strong	Altered Expression	[6]
Autosomal dominant auditory neuropathy 1	DISPY0YJ	Moderate	Autosomal dominant	[7]
Hearing loss, autosomal recessive	DIS8G9R9	moderate	Genetic Variation	[8]
Laryngeal squamous cell carcinoma	DIS9UUVF	moderate	Biomarker	[9]
Prostate carcinoma	DISMJPLE	moderate	Biomarker	[6]
Autosomal dominant nonsyndromic hearing loss	DISYC1G0	Supportive	Autosomal dominant	[10]
Acute myelogenous leukaemia	DISCSPTN	Limited	Genetic Variation	[11]
Adult glioblastoma	DISVP4LU	Limited	Biomarker	[12]
Auditory neuropathy	DISM6GAU	Limited	Autosomal dominant	[13]
Breast cancer	DIS7DPX1	Limited	Altered Expression	[14]
Breast carcinoma	DIS2UE88	Limited	Altered Expression	[14]
Glioblastoma multiforme	DISK8246	Limited	Biomarker	[12]
Hepatocellular carcinoma	DIS0J828	Limited	Altered Expression	[15]
Prostate cancer	DISF190Y	Limited	Biomarker	[6]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Valproate	DMCFE9I	Approved	Valproate decreases the methylation of Protein diaphanous homolog 3 (DIAPH3).	[16]
PMID28870136-Compound-52	DMFDERP	Patented	PMID28870136-Compound-52 decreases the phosphorylation of Protein diaphanous homolog 3 (DIAPH3).	[37]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A increases the methylation of Protein diaphanous homolog 3 (DIAPH3).	[38]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Ciclosporin	DMAZJFX	Approved	Ciclosporin decreases the expression of Protein diaphanous homolog 3 (DIAPH3).	[17]
Tretinoin	DM49DUI	Approved	Tretinoin decreases the expression of Protein diaphanous homolog 3 (DIAPH3).	[18]
Acetaminophen	DMUIE76	Approved	Acetaminophen decreases the expression of Protein diaphanous homolog 3 (DIAPH3).	[19]
Cupric Sulfate	DMP0NFQ	Approved	Cupric Sulfate increases the expression of Protein diaphanous homolog 3 (DIAPH3).	[20]
Cisplatin	DMRHGI9	Approved	Cisplatin decreases the expression of Protein diaphanous homolog 3 (DIAPH3).	[21]
Temozolomide	DMKECZD	Approved	Temozolomide increases the expression of Protein diaphanous homolog 3 (DIAPH3).	[22]
Arsenic trioxide	DM61TA4	Approved	Arsenic trioxide increases the expression of Protein diaphanous homolog 3 (DIAPH3).	[23]
Calcitriol	DM8ZVJ7	Approved	Calcitriol decreases the expression of Protein diaphanous homolog 3 (DIAPH3).	[24]
Testosterone	DM7HUNW	Approved	Testosterone decreases the expression of Protein diaphanous homolog 3 (DIAPH3).	[24]
Marinol	DM70IK5	Approved	Marinol increases the expression of Protein diaphanous homolog 3 (DIAPH3).	[25]
Zoledronate	DMIXC7G	Approved	Zoledronate decreases the expression of Protein diaphanous homolog 3 (DIAPH3).	[26]
Progesterone	DMUY35B	Approved	Progesterone decreases the expression of Protein diaphanous homolog 3 (DIAPH3).	[27]
Troglitazone	DM3VFPD	Approved	Troglitazone decreases the expression of Protein diaphanous homolog 3 (DIAPH3).	[28]
Azathioprine	DMMZSXQ	Approved	Azathioprine decreases the expression of Protein diaphanous homolog 3 (DIAPH3).	[29]
Dasatinib	DMJV2EK	Approved	Dasatinib decreases the expression of Protein diaphanous homolog 3 (DIAPH3).	[30]
Lucanthone	DMZLBUO	Approved	Lucanthone decreases the expression of Protein diaphanous homolog 3 (DIAPH3).	[31]
Urethane	DM7NSI0	Phase 4	Urethane increases the expression of Protein diaphanous homolog 3 (DIAPH3).	[32]
GSK2110183	DMZHB37	Phase 2	GSK2110183 decreases the expression of Protein diaphanous homolog 3 (DIAPH3).	[33]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene decreases the expression of Protein diaphanous homolog 3 (DIAPH3).	[34]
(+)-JQ1	DM1CZSJ	Phase 1	(+)-JQ1 decreases the expression of Protein diaphanous homolog 3 (DIAPH3).	[35]
PMID28460551-Compound-2	DM4DOUB	Patented	PMID28460551-Compound-2 decreases the expression of Protein diaphanous homolog 3 (DIAPH3).	[36]
Formaldehyde	DM7Q6M0	Investigative	Formaldehyde decreases the expression of Protein diaphanous homolog 3 (DIAPH3).	[39]
2-AMINO-1-METHYL-6-PHENYLIMIDAZO[4,5-B]PYRIDINE	DMNQL17	Investigative	2-AMINO-1-METHYL-6-PHENYLIMIDAZO[4,5-B]PYRIDINE increases the expression of Protein diaphanous homolog 3 (DIAPH3).	[40]

References

• [1] A double hit implicates DIAPH3 as an autism risk gene.Mol Psychiatry. 2011 Apr;16(4):442-51. doi: 10.1038/mp.2010.26. Epub 2010 Mar 23.
• [2] An mDia2/ROCK signaling axis regulates invasive egress from epithelial ovarian cancer spheroids.PLoS One. 2014 Feb 28;9(2):e90371. doi: 10.1371/journal.pone.0090371. eCollection 2014.
• [3] DIAPH3 promotes the tumorigenesis of lung adenocarcinoma.Exp Cell Res. 2019 Dec 1;385(1):111662. doi: 10.1016/j.yexcr.2019.111662. Epub 2019 Oct 3.
• [4] Enhanced shedding of extracellular vesicles from amoeboid prostate cancer cells: potential effects on the tumor microenvironment.Cancer Biol Ther. 2014 Apr;15(4):409-18. doi: 10.4161/cbt.27627. Epub 2014 Jan 14.
• [5] Oncosome formation in prostate cancer: association with a region of frequent chromosomal deletion in metastatic disease.Cancer Res. 2009 Jul 1;69(13):5601-9. doi: 10.1158/0008-5472.CAN-08-3860. Epub 2009 Jun 23.
• [6] Diaphanous-related formin-3 overexpression inhibits the migration and invasion of triple-negative breast cancer by inhibiting RhoA-GTP expression.Biomed Pharmacother. 2017 Oct;94:439-445. doi: 10.1016/j.biopha.2017.07.119. Epub 2017 Aug 2.
• [7] Diaphanous homolog 3 (Diap3) overexpression causes progressive hearing loss and inner hair cell defects in a transgenic mouse model of human deafness. PLoS One. 2013;8(2):e56520. doi: 10.1371/journal.pone.0056520. Epub 2013 Feb 18.
• [8] Molecular study of patients with auditory neuropathy.Mol Med Rep. 2016 Jul;14(1):481-90. doi: 10.3892/mmr.2016.5226. Epub 2016 May 9.
• [9] DIAPH2 alterations increase cellular motility and may contribute to the metastatic potential of laryngeal squamous cell carcinoma.Carcinogenesis. 2019 Oct 16;40(10):1251-1259. doi: 10.1093/carcin/bgz035.
• [10] Increased activity of Diaphanous homolog 3 (DIAPH3)/diaphanous causes hearing defects in humans with auditory neuropathy and in Drosophila. Proc Natl Acad Sci U S A. 2010 Jul 27;107(30):13396-401. doi: 10.1073/pnas.1003027107. Epub 2010 Jul 12.
• [11] Genome-wide haplotype association study identify the FGFR2 gene as a risk gene for acute myeloid leukemia.Oncotarget. 2017 Jan 31;8(5):7891-7899. doi: 10.18632/oncotarget.13631.
• [12] Differential Toxicity of mDia Formin-Directed Functional Agonists and Antagonists in Developing Zebrafish.Front Pharmacol. 2018 Apr 10;9:340. doi: 10.3389/fphar.2018.00340. eCollection 2018.
• [13] Technical standards for the interpretation and reporting of constitutional copy-number variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics (ACMG) and the Clinical Genome Resource (ClinGen). Genet Med. 2020 Feb;22(2):245-257. doi: 10.1038/s41436-019-0686-8. Epub 2019 Nov 6.
• [14] Regulation of microtubule dynamics by DIAPH3 influences amoeboid tumor cell mechanics and sensitivity to taxanes.Sci Rep. 2015 Jul 16;5:12136. doi: 10.1038/srep12136.
• [15] DIAPH3 promoted the growth, migration and metastasis of hepatocellular carcinoma cells by activating beta-catenin/TCF signaling.Mol Cell Biochem. 2018 Jan;438(1-2):183-190. doi: 10.1007/s11010-017-3125-7. Epub 2017 Aug 9.
• [16] 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.
• [17] Integrative "-Omics" analysis in primary human hepatocytes unravels persistent mechanisms of cyclosporine A-induced cholestasis. Chem Res Toxicol. 2016 Dec 19;29(12):2164-2174.
• [18] 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.
• [19] Multiple microRNAs function as self-protective modules in acetaminophen-induced hepatotoxicity in humans. Arch Toxicol. 2018 Feb;92(2):845-858.
• [20] Physiological and toxicological transcriptome changes in HepG2 cells exposed to copper. Physiol Genomics. 2009 Aug 7;38(3):386-401.
• [21] Activation of AIFM2 enhances apoptosis of human lung cancer cells undergoing toxicological stress. Toxicol Lett. 2016 Sep 6;258:227-236.
• [22] Temozolomide induces activation of Wnt/-catenin signaling in glioma cells via PI3K/Akt pathway: implications in glioma therapy. Cell Biol Toxicol. 2020 Jun;36(3):273-278. doi: 10.1007/s10565-019-09502-7. Epub 2019 Nov 22.
• [23] Essential role of cell cycle regulatory genes p21 and p27 expression in inhibition of breast cancer cells by arsenic trioxide. Med Oncol. 2011 Dec;28(4):1225-54.
• [24] Effects of 1alpha,25 dihydroxyvitamin D3 and testosterone on miRNA and mRNA expression in LNCaP cells. Mol Cancer. 2011 May 18;10:58.
• [25] THC exposure of human iPSC neurons impacts genes associated with neuropsychiatric disorders. Transl Psychiatry. 2018 Apr 25;8(1):89. doi: 10.1038/s41398-018-0137-3.
• [26] Interleukin-19 as a translational indicator of renal injury. Arch Toxicol. 2015 Jan;89(1):101-6.
• [27] Effects of progesterone treatment on expression of genes involved in uterine quiescence. Reprod Sci. 2011 Aug;18(8):781-97.
• [28] Effects of ciglitazone and troglitazone on the proliferation of human stomach cancer cells. World J Gastroenterol. 2009 Jan 21;15(3):310-20.
• [29] A transcriptomics-based in vitro assay for predicting chemical genotoxicity in vivo. Carcinogenesis. 2012 Jul;33(7):1421-9.
• [30] Dasatinib reverses cancer-associated fibroblasts (CAFs) from primary lung carcinomas to a phenotype comparable to that of normal fibroblasts. Mol Cancer. 2010 Jun 27;9:168.
• [31] Lucanthone is a novel inhibitor of autophagy that induces cathepsin D-mediated apoptosis. J Biol Chem. 2011 Feb 25;286(8):6602-13.
• [32] Ethyl carbamate induces cell death through its effects on multiple metabolic pathways. Chem Biol Interact. 2017 Nov 1;277:21-32.
• [33] Novel ATP-competitive Akt inhibitor afuresertib suppresses the proliferation of malignant pleural mesothelioma cells. Cancer Med. 2017 Nov;6(11):2646-2659. doi: 10.1002/cam4.1179. Epub 2017 Sep 27.
• [34] 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.
• [35] Inhibition of BRD4 attenuates tumor cell self-renewal and suppresses stem cell signaling in MYC driven medulloblastoma. Oncotarget. 2014 May 15;5(9):2355-71.
• [36] 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.
• [37] 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.
• [38] 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.
• [39] Characterization of formaldehyde's genotoxic mode of action by gene expression analysis in TK6 cells. Arch Toxicol. 2013 Nov;87(11):1999-2012.
• [40] Preferential induction of the AhR gene battery in HepaRG cells after a single or repeated exposure to heterocyclic aromatic amines. Toxicol Appl Pharmacol. 2010 Nov 15;249(1):91-100.