Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OT87DXEG)

• DOT Name: Dixin (DIXDC1)
• Synonyms: Coiled-coil protein DIX1; Coiled-coil-DIX1; DIX domain-containing protein 1
• Gene Name: DIXDC1
• Related Disease:
  Advanced cancer
  Prostate cancer
  Prostate carcinoma
  Acute myelogenous leukaemia
  Adult lymphoma
  Anxiety disorder
  Autism
  Bipolar depression
  Bipolar disorder
  Classic Hodgkin lymphoma
  Colon cancer
  Colon carcinoma
  Depression
  Glioma
  Hepatocellular carcinoma
  Lung cancer
  Lung carcinoma
  Lymphoma
  Neoplasm
  Non-hodgkin lymphoma
  Pediatric lymphoma
  Retinoblastoma
  Schizophrenia
  Gastric cancer
  Stomach cancer
• UniProt ID: DIXC1_HUMAN
• PDB ID: 3PZ7
• Pfam ID: PF00307 ; PF00778
• Sequence:
  MLACLTRGNLLDVLQEGFNEQQLQAYVAWVNAQLKKRPAVKPVQDLRQDLRDGVILAYLI
  EIVAGEKLSGVQLSPGNQQEMKNNVEKVLQFVASKKIRMHQTSAKDIVDGNLKSIMRLVL
  ALAAHFKPGSSRTVNQGRDSRAPLQSHRPHCATAVAQGAAAALADVCHDMSRSGRDVFRY
  RQRNSSMDEEIENPYWSVRALVQQYEGQQRSPSESSCSSLTSPSPIHSAKSESIITQSEE
  KADFVIIPAEGIENRTEGTDSPLSRDWRPGSPGTYLETSWEEQLLEQQEYLEKEMEEAKK
  MISGLQALLLNGSLPEDEQERPLALCEPGVNPEEQLIIIQSRLDQSMEENQDLKKELLKC
  KQEARNLQGIKDALQQRLTQQDTSVLQLKQELLRANMDKDELHNQNVDLQRKLDERNRLL
  GEYKKELGQKDRLLQQHQAKLEEALRKLSDVSYHQVDLERELEHKDVLLAHCMKREADEA
  TNYNSHNSQSNGFLLPTAGKGATSVSNRGTSDLQLVRDALRSLRNSFSGHDPQHHTIDSL
  EQGISSLMERLHVMETQKKQERKVRVKSPRTQVGSEYRESWPPNSKLPHSQSSPTVSSTC
  TKVLYFTDRSLTPFMVNIPKRLEEVTLKDFKAAIDREGNHRYHFKALDPEFGTVKEEIFH
  DDDAIPGWEGKIVAWVEEDHGEN
• Function: Positive effector of the Wnt signaling pathway; activates WNT3A signaling via DVL2. Regulates JNK activation by AXIN1 and DVL2.
• Tissue Specificity: Ubiquitously expressed with higher expression in cardiac and skeletal muscles.

Molecular Interaction Atlas (MIA) of This DOT

25 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Advanced cancer	DISAT1Z9	Definitive	Biomarker	[1]
Prostate cancer	DISF190Y	Definitive	Altered Expression	[1]
Prostate carcinoma	DISMJPLE	Definitive	Altered Expression	[1]
Acute myelogenous leukaemia	DISCSPTN	Strong	Altered Expression	[2]
Adult lymphoma	DISK8IZR	Strong	Biomarker	[3]
Anxiety disorder	DISBI2BT	Strong	Biomarker	[4]
Autism	DISV4V1Z	Strong	Biomarker	[4]
Bipolar depression	DISA75FU	Strong	Biomarker	[4]
Bipolar disorder	DISAM7J2	Strong	Biomarker	[4]
Classic Hodgkin lymphoma	DISV1LU6	Strong	Biomarker	[3]
Colon cancer	DISVC52G	Strong	Altered Expression	[5]
Colon carcinoma	DISJYKUO	Strong	Altered Expression	[5]
Depression	DIS3XJ69	Strong	Biomarker	[4]
Glioma	DIS5RPEH	Strong	Altered Expression	[6]
Hepatocellular carcinoma	DIS0J828	Strong	Altered Expression	[7]
Lung cancer	DISCM4YA	Strong	Altered Expression	[8]
Lung carcinoma	DISTR26C	Strong	Altered Expression	[8]
Lymphoma	DISN6V4S	Strong	Biomarker	[3]
Neoplasm	DISZKGEW	Strong	Altered Expression	[7]
Non-hodgkin lymphoma	DISS2Y8A	Strong	Altered Expression	[3]
Pediatric lymphoma	DIS51BK2	Strong	Biomarker	[3]
Retinoblastoma	DISVPNPB	Strong	Altered Expression	[9]
Schizophrenia	DISSRV2N	Strong	Biomarker	[4]
Gastric cancer	DISXGOUK	Limited	Biomarker	[10]
Stomach cancer	DISKIJSX	Limited	Biomarker	[10]

4 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 Dixin (DIXDC1).	[11]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene affects the methylation of Dixin (DIXDC1).	[17]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A increases the methylation of Dixin (DIXDC1).	[20]
Coumarin	DM0N8ZM	Investigative	Coumarin increases the phosphorylation of Dixin (DIXDC1).	[22]

9 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 Dixin (DIXDC1).	[12]
Estradiol	DMUNTE3	Approved	Estradiol decreases the expression of Dixin (DIXDC1).	[13]
Triclosan	DMZUR4N	Approved	Triclosan decreases the expression of Dixin (DIXDC1).	[14]
Isotretinoin	DM4QTBN	Approved	Isotretinoin increases the expression of Dixin (DIXDC1).	[15]
Ethanol	DMDRQZU	Approved	Ethanol increases the expression of Dixin (DIXDC1).	[16]
Leflunomide	DMR8ONJ	Phase 1 Trial	Leflunomide increases the expression of Dixin (DIXDC1).	[18]
PMID28460551-Compound-2	DM4DOUB	Patented	PMID28460551-Compound-2 decreases the expression of Dixin (DIXDC1).	[19]
Trichostatin A	DM9C8NX	Investigative	Trichostatin A affects the expression of Dixin (DIXDC1).	[21]
Coumestrol	DM40TBU	Investigative	Coumestrol decreases the expression of Dixin (DIXDC1).	[23]

References

• [1] Inhibition of DIXDC1 by microRNA-1271 suppresses the proliferation and invasion of prostate cancer cells.Biochem Biophys Res Commun. 2017 Mar 18;484(4):794-800. doi: 10.1016/j.bbrc.2017.01.169. Epub 2017 Jan 31.
• [2] DIXDC1 promotes the growth of acute myeloid leukemia cells by upregulating the Wnt/-catenin signaling pathway.Biomed Pharmacother. 2018 Nov;107:1548-1555. doi: 10.1016/j.biopha.2018.08.144. Epub 2018 Sep 5.
• [3] DIXDC1 promotes tumor proliferation and cell adhesion mediated drug resistance (CAM-DR) via enhancing p-Akt in Non-Hodgkin's lymphomas.Leuk Res. 2016 Nov;50:104-111. doi: 10.1016/j.leukres.2016.09.011. Epub 2016 Sep 8.
• [4] DIXDC1 contributes to psychiatric susceptibility by regulating dendritic spine and glutamatergic synapse density via GSK3 and Wnt/-catenin signaling.Mol Psychiatry. 2018 Feb;23(2):467-475. doi: 10.1038/mp.2016.184. Epub 2016 Oct 18.
• [5] DIXDC1 targets p21 and cyclin D1 via PI3K pathway activation to promote colon cancer cell proliferation.Cancer Sci. 2009 Oct;100(10):1801-8. doi: 10.1111/j.1349-7006.2009.01246.x. Epub 2009 Jun 17.
• [6] Knockdown of DIXDC1 Inhibits the Proliferation and Migration of Human Glioma Cells.Cell Mol Neurobiol. 2017 Aug;37(6):1009-1019. doi: 10.1007/s10571-016-0433-5. Epub 2016 Nov 5.
• [7] Downregulated expression of DIXDC1 in hepatocellular carcinoma and its correlation with prognosis.Tumour Biol. 2016 Oct;37(10):13607-13616. doi: 10.1007/s13277-016-5213-9. Epub 2016 Jul 28.
• [8] KIAA1735 gene on human chromosome 11q23.1 encodes a novel protein with myosine-tail homologous domain and C-terminal DIX domain.Int J Oncol. 2003 Jul;23(1):145-50.
• [9] Suppression of Disheveled-Axin Domain Containing 1 (DIXDC1) by MicroRNA-186 Inhibits the Proliferation and Invasion of Retinoblastoma Cells.J Mol Neurosci. 2018 Feb;64(2):252-261. doi: 10.1007/s12031-017-1017-7. Epub 2017 Dec 20.
• [10] MicroRNA-154 Inhibits the Growth and Invasion of Gastric Cancer Cells by Targeting DIXDC1/WNT Signaling.Oncol Res. 2018 Jul 5;26(6):847-856. doi: 10.3727/096504017X15016337254632. Epub 2017 Aug 11.
• [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] Integrating multiple omics to unravel mechanisms of Cyclosporin A induced hepatotoxicity in vitro. Toxicol In Vitro. 2015 Apr;29(3):489-501.
• [13] High-throughput ectopic expression screen for tamoxifen resistance identifies an atypical kinase that blocks autophagy. Proc Natl Acad Sci U S A. 2011 Feb 1;108(5):2058-63.
• [14] Transcriptome and DNA methylome dynamics during triclosan-induced cardiomyocyte differentiation toxicity. Stem Cells Int. 2018 Oct 29;2018:8608327.
• [15] Temporal changes in gene expression in the skin of patients treated with isotretinoin provide insight into its mechanism of action. Dermatoendocrinol. 2009 May;1(3):177-87.
• [16] Gene expression signatures after ethanol exposure in differentiating embryoid bodies. Toxicol In Vitro. 2018 Feb;46:66-76.
• [17] 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.
• [18] Endoplasmic reticulum stress and MAPK signaling pathway activation underlie leflunomide-induced toxicity in HepG2 Cells. Toxicology. 2017 Dec 1;392:11-21.
• [19] 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.
• [20] 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.
• [21] A trichostatin A expression signature identified by TempO-Seq targeted whole transcriptome profiling. PLoS One. 2017 May 25;12(5):e0178302. doi: 10.1371/journal.pone.0178302. eCollection 2017.
• [22] 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.
• [23] Pleiotropic combinatorial transcriptomes of human breast cancer cells exposed to mixtures of dietary phytoestrogens. Food Chem Toxicol. 2009 Apr;47(4):787-95.