Details of Drug Off-Target (DOT)

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

• DOT Name: MORC family CW-type zinc finger protein 4 (MORC4)
• Synonyms: Zinc finger CW-type coiled-coil domain protein 2; Zinc finger CW-type domain protein 4
• Gene Name: MORC4
• Related Disease:
  B-cell lymphoma
  Chronic pancreatitis
  Classic Hodgkin lymphoma
  Crohn disease
  Inflammatory bowel disease
  Pancreatitis
  Breast cancer
  Breast carcinoma
• UniProt ID: MORC4_HUMAN
• PDB ID: 7K7T
• Pfam ID: PF13589 ; PF17942 ; PF07496
• Sequence:
  MLLYRGAPAGPGAPGCGLARPGGGPQAFGIRLSTMSPRYLQSNSSSHTRPFSAIAELLDN
  AVDPDVSARTVFIDVEEVKNKSCLTFTDDGCGMTPHKLHRMLSFGFTDKVIKKSQCPIGV
  FGNGFKSGSMRLGKDALVFTKNGGTLTVGLLSQTYLECVQAQAVIVPIVPFNQQNKKMII
  TEDSLPSLEAILNYSIFNRENDLLAQFDAIPGKKGTRVLIWNIRRNKNGKSELDFDTDQY
  DILVSDFDTEEKMTGGVTSELPETEYSLRAFCGILYMKPRMKIFLRQKKVTTQMIAKSLA
  NVEYDTYKPTFTNKQVRITFGFSCKNSNQFGIMMYHNNRLIKSFEKVGCQVKPTRGEGVG
  VIGVIECNFLKPAYNKQDFEYTKEYRLTINALAQKLNAYWKEKTSQDNFETSTVARPIPK
  VPDQTWVQCDECLKWRKLPGKIDPSMLPARWFCYYNSHPKYRRCSVPEEQELTDEDLCLS
  KAKKQEQTVEEKKKMPMENENHQVFSNPPKILTVQEMAGLNNKTIGYEGIHSPSVLPSGG
  EESRSPSLQLKPLDSSVLQFSSKYKWILGEEPVEKRRRLQNEMTTPSLDYSMPAPYRRVE
  APVAYPEGENSHDKSSSERSTPPYLFPEYPEASKNTGQNREVSILYPGAKDQRQGSLLPE
  ELEDQMPRLVAEESNRGSTTINKEEVNKGPFVAVVGVAKGVRDSGAPIQLIPFNREELAE
  RRKAVESWNPVPYSVASAAIPAAAIGEKARGYEESEGHNTPKLKNQRELEELKRTTEKLE
  RVLAERNLFQQKVEELEQERNHWQSEFKKVQHELVIYSTQEAEGLYWSKKHMGYRQAEFQ
  ILKAELERTKEEKQELKEKLKETETHLEMLQKAQVSYRTPEGDDLERALAKLTRLRIHVS
  YLLTSVLPHLELREIGYDSEQVDGILYTVLEANHILD
• Function: Histone methylation reader which binds to non-methylated (H3K4me0), monomethylated (H3K4me1), dimethylated (H3K4me2) and trimethylated (H3K4me3) 'Lys-4' on histone H3. The order of binding preference is H3K4me3 > H3K4me2 > H3K4me1 > H3K4me0.
• Tissue Specificity: Expressed at low levels in normal tissues, with highest expression levels in placenta and testis. Expression is significantly increased in subset of diffuse large B-cell lymphomas.

Molecular Interaction Atlas (MIA) of This DOT

8 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
B-cell lymphoma	DISIH1YQ	Strong	Biomarker	[1]
Chronic pancreatitis	DISBUOMJ	Strong	Genetic Variation	[2]
Classic Hodgkin lymphoma	DISV1LU6	Strong	Altered Expression	[1]
Crohn disease	DIS2C5Q8	Strong	Genetic Variation	[3]
Inflammatory bowel disease	DISGN23E	Strong	Genetic Variation	[3]
Pancreatitis	DIS0IJEF	Strong	Genetic Variation	[4]
Breast cancer	DIS7DPX1	moderate	Altered Expression	[5]
Breast carcinoma	DIS2UE88	moderate	Altered Expression	[5]

This DOT Affected the Drug Response of 1 Drug(s)

Drug Name	Drug ID	Highest Status	Interaction	REF
Ethanol	DMDRQZU	Approved	MORC family CW-type zinc finger protein 4 (MORC4) increases the Alcoholic pancreatitis ADR of Ethanol.	[18]

3 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 MORC family CW-type zinc finger protein 4 (MORC4).	[6]
Arsenic	DMTL2Y1	Approved	Arsenic affects the methylation of MORC family CW-type zinc finger protein 4 (MORC4).	[12]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene increases the methylation of MORC family CW-type zinc finger protein 4 (MORC4).	[16]

10 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 MORC family CW-type zinc finger protein 4 (MORC4).	[7]
Tretinoin	DM49DUI	Approved	Tretinoin increases the expression of MORC family CW-type zinc finger protein 4 (MORC4).	[8]
Acetaminophen	DMUIE76	Approved	Acetaminophen increases the expression of MORC family CW-type zinc finger protein 4 (MORC4).	[9]
Cupric Sulfate	DMP0NFQ	Approved	Cupric Sulfate increases the expression of MORC family CW-type zinc finger protein 4 (MORC4).	[10]
Cisplatin	DMRHGI9	Approved	Cisplatin increases the expression of MORC family CW-type zinc finger protein 4 (MORC4).	[11]
Quercetin	DM3NC4M	Approved	Quercetin increases the expression of MORC family CW-type zinc finger protein 4 (MORC4).	[13]
Hydrogen peroxide	DM1NG5W	Approved	Hydrogen peroxide affects the expression of MORC family CW-type zinc finger protein 4 (MORC4).	[14]
Testosterone	DM7HUNW	Approved	Testosterone decreases the expression of MORC family CW-type zinc finger protein 4 (MORC4).	[15]
Menadione	DMSJDTY	Approved	Menadione affects the expression of MORC family CW-type zinc finger protein 4 (MORC4).	[14]
PMID28460551-Compound-2	DM4DOUB	Patented	PMID28460551-Compound-2 increases the expression of MORC family CW-type zinc finger protein 4 (MORC4).	[17]

References

• [1] MORC4, a novel member of the MORC family, is highly expressed in a subset of diffuse large B-cell lymphomas.Br J Haematol. 2007 Aug;138(4):479-86. doi: 10.1111/j.1365-2141.2007.06680.x. Epub 2007 Jun 29.
• [2] Do pancreatic cancer and chronic pancreatitis share the same genetic risk factors? A PANcreatic Disease ReseArch (PANDoRA) consortium investigation.Int J Cancer. 2018 Jan 15;142(2):290-296. doi: 10.1002/ijc.31047. Epub 2017 Oct 16.
• [3] Analysis of single nucleotide polymorphisms in the region of CLDN2-MORC4 in relation to inflammatory bowel disease.World J Gastroenterol. 2013 Aug 14;19(30):4935-43. doi: 10.3748/wjg.v19.i30.4935.
• [4] Effects of PRSS1-PRSS2 rs10273639, CLDN2 rs7057398 and MORC4 rs12688220 polymorphisms on individual susceptibility to pancreatitis: A meta-analysis.Genomics. 2020 Jan;112(1):848-852. doi: 10.1016/j.ygeno.2019.05.025. Epub 2019 Jun 1.
• [5] MORC4 is a novel breast cancer oncogene regulated by miR-193b-3p.J Cell Biochem. 2019 Mar;120(3):4634-4643. doi: 10.1002/jcb.27751. Epub 2018 Oct 15.
• [6] 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.
• [7] 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.
• [8] 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.
• [9] 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.
• [10] Physiological and toxicological transcriptome changes in HepG2 cells exposed to copper. Physiol Genomics. 2009 Aug 7;38(3):386-401.
• [11] Activation of AIFM2 enhances apoptosis of human lung cancer cells undergoing toxicological stress. Toxicol Lett. 2016 Sep 6;258:227-236.
• [12] 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.
• [13] 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.
• [14] Global gene expression analysis reveals differences in cellular responses to hydroxyl- and superoxide anion radical-induced oxidative stress in caco-2 cells. Toxicol Sci. 2010 Apr;114(2):193-203. doi: 10.1093/toxsci/kfp309. Epub 2009 Dec 31.
• [15] The exosome-like vesicles derived from androgen exposed-prostate stromal cells promote epithelial cells proliferation and epithelial-mesenchymal transition. Toxicol Appl Pharmacol. 2021 Jan 15;411:115384. doi: 10.1016/j.taap.2020.115384. Epub 2020 Dec 25.
• [16] 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.
• [17] 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.
• [18] Common genetic variants in the CLDN2 and PRSS1-PRSS2 loci alter risk for alcohol-related and sporadic pancreatitis. Nat Genet. 2012 Dec;44(12):1349-54. doi: 10.1038/ng.2466. Epub 2012 Nov 11.