Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTII2U6L)

• DOT Name: Capping protein-inhibiting regulator of actin dynamics (CRACD)
• Synonyms: Cancer-related regulator of actin dynamics
• Gene Name: CRACD
• Related Disease:
  Adenoma
  Colorectal carcinoma
  Melanoma
  Neoplasm
  Non-small-cell lung cancer
  Prostate cancer
  Small-cell lung cancer
• UniProt ID: CRACD_HUMAN
• Pfam ID: PF15262
• Sequence:
  MGTRAFSHDSIFIPDGGAESEQTVQAMSQDNILGKVKTLQQQLGKNIKFGQRSPNAIPMN
  KANSGEASLEEDLFLTSPMEIVTQQDIVLSDAENKSSDTPSSLSPLNLPGAGSEMEEKVA
  PVKPSRPKRHFSSAGTIESVNLDAIPLAIARLDNSAAKHKLAVKPKKQRVSKKHRRLAQD
  PQHEQGGLESRPCLDQNGHPGEDKPTWHEEEPNPLDSEEERRRQEDYWRELEAKCKRQKA
  EAAEKRRLEEQRLQALERRLWEENRRQELLEEEGEGQEPPLEAERAPREEQQRSLEAPGW
  EDAERREREERERLEAEEERRRLQAQAQAEERRRLEEDARLEERRRQEEEEGRCAEELKR
  QEEEEAEGWEELEQQEAEVQGPPEALEETGEGRRGAEEEDLGEEEEEGQAHLEDWRGQLS
  ELLNDFEERLEDQERLKPEGQREHSEEPGICEEQNPEAERRREQQGRSGDFQGADRPGPE
  EKREEGDTEPLLKQEGPVEAAQPPVERKEAAALEQGRKVEELRWQEVDERQTMPRPYTFQ
  VSSGGKQILFPKVNLSPVTPAKDTGLTAAPQEPKAPKASPVQHALPSSLSVPHTAILVTG
  AQLCGPAVNLSQIKDTACKSLLGLEEKKHAEAPAGENPPRGPGDARAGSGKAKPRQESPS
  SASALAEWASIRSRILKNAESDPRSSERDQLRPGDESTPRGRCDSRGNQRKTPPVNAKFS
  IMPAWQKFSDGGTETSKQSTEAESIRKRPMLGPSEETAPQPPPAGVRELGKGPEKSEMHR
  EPADTTEGCKFAKDLPSFLVPSLPYPPQKVVAHTEFTTSSDSETANGIAKPDPVMPGGEE
  KASPFGIKLRRTNYSLRFNCDQQAEQKKKKRHSSTGDSADAGPPAAGSARGEKEMEGVAL
  KHGPSLPQERKQAPSTRRDSAEPSSSRSVPVAHPGPPPASSQTPAPEHDKAANKMPLAQK
  PALAPKPTSQTPPASPLSKLSRPYLVELLSRRAGRPDPEPSEPSKEDQESSDRRPPSPPG
  PEERKGQKRDEEEEATERKPASPPLPATQQEKPSQTPEAGRKEKPMLQSRHSLDGSKLTE
  KVETAQPLWITLALQKQKGFREQQATREERKQAREAKQAEKLSKENVSVSVQPGSSSVSR
  AGSLHKSTALPEEKRPETAVSRLERREQLKKANTLPTSVTVEISDSAPPAPLVKEVTKRF
  STPDAAPVSTEPAWLALAKRKAKAWSDCPQIIK
• Function: Involved in epithelial cell integrity by acting on the maintenance of the actin cytoskeleton. Positively regulates the actin polymerization, by inhibiting the interaction of actin-capping proteins with actin.
• Tissue Specificity: Expressed in intestinal epithelial cells (at protein level).

Molecular Interaction Atlas (MIA) of This DOT

7 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Adenoma	DIS78ZEV	Strong	Genetic Variation	[1]
Colorectal carcinoma	DIS5PYL0	Strong	Biomarker	[1]
Melanoma	DIS1RRCY	Strong	Biomarker	[2]
Neoplasm	DISZKGEW	Strong	Biomarker	[3]
Non-small-cell lung cancer	DIS5Y6R9	Strong	Biomarker	[3]
Prostate cancer	DISF190Y	Strong	Genetic Variation	[4]
Small-cell lung cancer	DISK3LZD	moderate	Biomarker	[5]

5 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 Capping protein-inhibiting regulator of actin dynamics (CRACD).	[6]
Arsenic	DMTL2Y1	Approved	Arsenic affects the methylation of Capping protein-inhibiting regulator of actin dynamics (CRACD).	[8]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene decreases the methylation of Capping protein-inhibiting regulator of actin dynamics (CRACD).	[11]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A decreases the methylation of Capping protein-inhibiting regulator of actin dynamics (CRACD).	[14]
Coumarin	DM0N8ZM	Investigative	Coumarin affects the phosphorylation of Capping protein-inhibiting regulator of actin dynamics (CRACD).	[16]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Cisplatin	DMRHGI9	Approved	Cisplatin decreases the expression of Capping protein-inhibiting regulator of actin dynamics (CRACD).	[7]
Quercetin	DM3NC4M	Approved	Quercetin decreases the expression of Capping protein-inhibiting regulator of actin dynamics (CRACD).	[9]
Marinol	DM70IK5	Approved	Marinol increases the expression of Capping protein-inhibiting regulator of actin dynamics (CRACD).	[10]
(+)-JQ1	DM1CZSJ	Phase 1	(+)-JQ1 decreases the expression of Capping protein-inhibiting regulator of actin dynamics (CRACD).	[12]
PMID28460551-Compound-2	DM4DOUB	Patented	PMID28460551-Compound-2 decreases the expression of Capping protein-inhibiting regulator of actin dynamics (CRACD).	[13]
Trichostatin A	DM9C8NX	Investigative	Trichostatin A increases the expression of Capping protein-inhibiting regulator of actin dynamics (CRACD).	[15]
Coumestrol	DM40TBU	Investigative	Coumestrol decreases the expression of Capping protein-inhibiting regulator of actin dynamics (CRACD).	[17]

References

• [1] Deregulation of CRAD-controlled cytoskeleton initiates mucinous colorectal cancer via -catenin.Nat Cell Biol. 2018 Nov;20(11):1303-1314. doi: 10.1038/s41556-018-0215-z. Epub 2018 Oct 22.
• [2] Conditionally replication-competent adenoviral vectors with enhanced infectivity for use in gene therapy of melanoma.Hum Gene Ther. 2004 Jul;15(7):637-47. doi: 10.1089/1043034041361181.
• [3] KIAA1211 plays an oncogenic role in human non-small cell lung cancer.J Cancer. 2019 Oct 22;10(26):6747-6753. doi: 10.7150/jca.35951. eCollection 2019.
• [4] Two genome-wide association studies of aggressive prostate cancer implicate putative prostate tumor suppressor gene DAB2IP.J Natl Cancer Inst. 2007 Dec 19;99(24):1836-44. doi: 10.1093/jnci/djm250. Epub 2007 Dec 11.
• [5] Prognostic impact of tumor mutation burden and the mutation in KIAA1211 in small cell lung cancer.Respir Res. 2019 Nov 7;20(1):248. doi: 10.1186/s12931-019-1205-9.
• [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] Activation of AIFM2 enhances apoptosis of human lung cancer cells undergoing toxicological stress. Toxicol Lett. 2016 Sep 6;258:227-236.
• [8] 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.
• [9] 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.
• [10] 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.
• [11] 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.
• [12] CCAT1 is an enhancer-templated RNA that predicts BET sensitivity in colorectal cancer. J Clin Invest. 2016 Feb;126(2):639-52.
• [13] 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.
• [14] 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.
• [15] 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.
• [16] 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.
• [17] Pleiotropic combinatorial transcriptomes of human breast cancer cells exposed to mixtures of dietary phytoestrogens. Food Chem Toxicol. 2009 Apr;47(4):787-95.