Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTYH9NRJ)

• DOT Name: Cytohesin-1 (CYTH1)
• Synonyms: PH, SEC7 and coiled-coil domain-containing protein 1; SEC7 homolog B2-1
• Gene Name: CYTH1
• Related Disease:
  Autism
  Intellectual disability
  Acute leukaemia
  Atrial fibrillation
  Immunodeficiency
  Familial atrial fibrillation
  Prostate cancer
  Prostate carcinoma
  Ulcerative colitis
• UniProt ID: CYH1_HUMAN
• PDB ID: 1BC9; 4A4P
• Pfam ID: PF00169 ; PF01369
• Sequence:
  MEEDDSYVPSDLTAEERQELENIRRRKQELLADIQRLKDEIAEVANEIENLGSTEERKNM
  QRNKQVAMGRKKFNMDPKKGIQFLIENDLLKNTCEDIAQFLYKGEGLNKTAIGDYLGERD
  EFNIQVLHAFVELHEFTDLNLVQALRQFLWSFRLPGEAQKIDRMMEAFAQRYCQCNNGVF
  QSTDTCYVLSFAIIMLNTSLHNPNVKDKPTVERFIAMNRGINDGGDLPEELLRNLYESIK
  NEPFKIPEDDGNDLTHTFFNPDREGWLLKLGGGRVKTWKRRWFILTDNCLYYFEYTTDKE
  PRGIIPLENLSIREVEDSKKPNCFELYIPDNKDQVIKACKTEADGRVVEGNHTVYRISAP
  TPEEKEEWIKCIKAAISRDPFYEMLAARKKKVSSTKRH
• Function: Promotes guanine-nucleotide exchange on ARF1, ARF5 and ARF6. Promotes the activation of ARF factors through replacement of GDP with GTP. Plays an important role in membrane trafficking, during junctional remodeling and epithelial polarization, through regulation of ARF6 activity.
• Tissue Specificity: Ubiquitous.
• KEGG Pathway:
  Phospholipase D sig.ling pathway (hsa04072)
  Endocytosis (hsa04144)
  Pathogenic Escherichia coli infection (hsa05130)
  Shigellosis (hsa05131)
  Salmonella infection (hsa05132)
• Reactome Pathway: Intra-Golgi traffic (R-HSA-6811438)

Molecular Interaction Atlas (MIA) of This DOT

9 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Autism	DISV4V1Z	Definitive	Altered Expression	[1]
Intellectual disability	DISMBNXP	Definitive	Altered Expression	[1]
Acute leukaemia	DISDQFDI	Strong	Biomarker	[2]
Atrial fibrillation	DIS15W6U	Strong	Biomarker	[3]
Immunodeficiency	DIS093I0	Strong	Biomarker	[4]
Familial atrial fibrillation	DISL4AGF	moderate	Biomarker	[3]
Prostate cancer	DISF190Y	moderate	Biomarker	[5]
Prostate carcinoma	DISMJPLE	moderate	Biomarker	[5]
Ulcerative colitis	DIS8K27O	moderate	Genetic Variation	[6]

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 Cytohesin-1 (CYTH1).	[7]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A decreases the methylation of Cytohesin-1 (CYTH1).	[22]

16 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 Cytohesin-1 (CYTH1).	[8]
Tretinoin	DM49DUI	Approved	Tretinoin increases the expression of Cytohesin-1 (CYTH1).	[9]
Acetaminophen	DMUIE76	Approved	Acetaminophen increases the expression of Cytohesin-1 (CYTH1).	[10]
Doxorubicin	DMVP5YE	Approved	Doxorubicin decreases the expression of Cytohesin-1 (CYTH1).	[11]
Cupric Sulfate	DMP0NFQ	Approved	Cupric Sulfate increases the expression of Cytohesin-1 (CYTH1).	[12]
Cisplatin	DMRHGI9	Approved	Cisplatin increases the expression of Cytohesin-1 (CYTH1).	[13]
Temozolomide	DMKECZD	Approved	Temozolomide increases the expression of Cytohesin-1 (CYTH1).	[14]
Cytarabine	DMZD5QR	Approved	Cytarabine increases the expression of Cytohesin-1 (CYTH1).	[15]
DTI-015	DMXZRW0	Approved	DTI-015 increases the expression of Cytohesin-1 (CYTH1).	[16]
Azacitidine	DMTA5OE	Approved	Azacitidine increases the expression of Cytohesin-1 (CYTH1).	[15]
Urethane	DM7NSI0	Phase 4	Urethane affects the expression of Cytohesin-1 (CYTH1).	[17]
Dihydrotestosterone	DM3S8XC	Phase 4	Dihydrotestosterone increases the expression of Cytohesin-1 (CYTH1).	[18]
SNDX-275	DMH7W9X	Phase 3	SNDX-275 decreases the expression of Cytohesin-1 (CYTH1).	[19]
Genistein	DM0JETC	Phase 2/3	Genistein decreases the expression of Cytohesin-1 (CYTH1).	[20]
Belinostat	DM6OC53	Phase 2	Belinostat decreases the expression of Cytohesin-1 (CYTH1).	[19]
Leflunomide	DMR8ONJ	Phase 1 Trial	Leflunomide increases the expression of Cytohesin-1 (CYTH1).	[21]

References

• [1] IQSEC2-Associated Intellectual Disability and Autism.Int J Mol Sci. 2019 Jun 21;20(12):3038. doi: 10.3390/ijms20123038.
• [2] The der(12)t(12;16) breakpoint in an acute leukaemia case targets a Sec7 domain containing protein.Int J Oncol. 2005 Apr;26(4):1111-20.
• [3] Multi-ethnic genome-wide association study for atrial fibrillation.Nat Genet. 2018 Jun 11;50(9):1225-1233. doi: 10.1038/s41588-018-0133-9.
• [4] Cytohesin 1 regulates homing and engraftment of human hematopoietic stem and progenitor cells.Blood. 2017 Feb 23;129(8):950-958. doi: 10.1182/blood-2016-06-720649. Epub 2016 Nov 29.
• [5] Inhibition of cytohesin-1 by siRNA leads to reduced IGFR signaling in prostate cancer.Braz J Med Biol Res. 2011 Jul;44(7):642-6. doi: 10.1590/s0100-879x2011007500072. Epub 2011 Jun 10.
• [6] Association analyses identify 38 susceptibility loci for inflammatory bowel disease and highlight shared genetic risk across populations.Nat Genet. 2015 Sep;47(9):979-986. doi: 10.1038/ng.3359. Epub 2015 Jul 20.
• [7] 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.
• [8] Evaluation of a human iPSC-derived BBB model for repeated dose toxicity testing with cyclosporine A as model compound. Toxicol In Vitro. 2021 Jun;73:105112. doi: 10.1016/j.tiv.2021.105112. Epub 2021 Feb 22.
• [9] Retinoic acid receptor alpha amplifications and retinoic acid sensitivity in breast cancers. Clin Breast Cancer. 2013 Oct;13(5):401-8.
• [10] 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.
• [11] 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.
• [12] Physiological and toxicological transcriptome changes in HepG2 cells exposed to copper. Physiol Genomics. 2009 Aug 7;38(3):386-401.
• [13] Low doses of cisplatin induce gene alterations, cell cycle arrest, and apoptosis in human promyelocytic leukemia cells. Biomark Insights. 2016 Aug 24;11:113-21.
• [14] 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.
• [15] The DNA methyltransferase inhibitors azacitidine, decitabine and zebularine exert differential effects on cancer gene expression in acute myeloid leukemia cells. Leukemia. 2009 Jun;23(6):1019-28.
• [16] Gene expression profile induced by BCNU in human glioma cell lines with differential MGMT expression. J Neurooncol. 2005 Jul;73(3):189-98.
• [17] Ethyl carbamate induces cell death through its effects on multiple metabolic pathways. Chem Biol Interact. 2017 Nov 1;277:21-32.
• [18] LSD1 activates a lethal prostate cancer gene network independently of its demethylase function. Proc Natl Acad Sci U S A. 2018 May 1;115(18):E4179-E4188.
• [19] 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.
• [20] Changes in gene expressions elicited by physiological concentrations of genistein on human endometrial cancer cells. Mol Carcinog. 2006 Oct;45(10):752-63.
• [21] Endoplasmic reticulum stress and MAPK signaling pathway activation underlie leflunomide-induced toxicity in HepG2 Cells. Toxicology. 2017 Dec 1;392:11-21.
• [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.