Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTV9AD0L)

• DOT Name: Protein APCDD1 (APCDD1)
• Synonyms: Adenomatosis polyposis coli down-regulated 1 protein
• Gene Name: APCDD1
• Related Disease:
  Malaria
  Advanced cancer
  Alzheimer disease
  B-cell lymphoma
  Breast cancer
  Breast carcinoma
  Charcot marie tooth disease
  Coagulation defect
  Colon cancer
  Colon carcinoma
  Fatty liver disease
  Hepatitis C virus infection
  High blood pressure
  Hypotrichosis 1
  Inherited bleeding disorder, platelet-type
  leukaemia
  Leukemia
  Metabolic disorder
  Multiple sclerosis
  Obesity
  Small lymphocytic lymphoma
  Hypotrichosis simplex
  Bone osteosarcoma
  Glioblastoma multiforme
  Melanoma
  Microphthalmia
  Neoplasm
  Osteosarcoma
  Stroke
• UniProt ID: APCD1_HUMAN
• Pfam ID: PF14921
• Sequence:
  MSWPRRLLLRYLFPALLLHGLGEGSALLHPDSRSHPRSLEKSAWRAFKESQCHHMLKHLH
  NGARITVQMPPTIEGHWVSTGCEVRSGPEFITRSYRFYHNNTFKAYQFYYGSNRCTNPTY
  TLIIRGKIRLRQASWIIRGGTEADYQLHNVQVICHTEAVAEKLGQQVNRTCPGFLADGGP
  WVQDVAYDLWREENGCECTKAVNFAMHELQLIRVEKQYLHHNLDHLVEELFLGDIHTDAT
  QRMFYRPSSYQPPLQNAKNHDHACIACRIIYRSDEHHPPILPPKADLTIGLHGEWVSQRC
  EVRPEVLFLTRHFIFHDNNNTWEGHYYHYSDPVCKHPTFSIYARGRYSRGVLSSRVMGGT
  EFVFKVNHMKVTPMDAATASLLNVFNGNECGAEGSWQVGIQQDVTHTNGCVALGIKLPHT
  EYEIFKMEQDARGRYLLFNGQRPSDGSSPDRPEKRATSYQMPLVQCASSSPRAEDLAEDS
  GSSLYGRAPGRHTWSLLLAALACLVPLLHWNIRR
• Function: Negative regulator of the Wnt signaling pathway. Inhibits Wnt signaling in a cell-autonomous manner and functions upstream of beta-catenin. May act via its interaction with Wnt and LRP proteins. May play a role in colorectal tumorigenesis.
• Tissue Specificity: Abundantly expressed in heart, pancreas, prostate and ovary. Moderately expressed in lung, liver, kidney, spleen, thymus, colon and peripheral lymphocytes. Abundantly expressed in both the epidermal and dermal compartments of the hair follicle. Present in scalp skin Highly expressed in the hair follicle dermal papilla, the matrix, and the hair shaft (at protein level).
• KEGG Pathway: Wnt sig.ling pathway (hsa04310)

Molecular Interaction Atlas (MIA) of This DOT

29 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Malaria	DISQ9Y50	Definitive	Biomarker	[1]
Advanced cancer	DISAT1Z9	Strong	Biomarker	[2]
Alzheimer disease	DISF8S70	Strong	Biomarker	[3]
B-cell lymphoma	DISIH1YQ	Strong	Biomarker	[4]
Breast cancer	DIS7DPX1	Strong	Biomarker	[5]
Breast carcinoma	DIS2UE88	Strong	Biomarker	[5]
Charcot marie tooth disease	DIS3BT2L	Strong	Biomarker	[6]
Coagulation defect	DIS9X3H6	Strong	Biomarker	[7]
Colon cancer	DISVC52G	Strong	Biomarker	[8]
Colon carcinoma	DISJYKUO	Strong	Biomarker	[8]
Fatty liver disease	DIS485QZ	Strong	Biomarker	[9]
Hepatitis C virus infection	DISQ0M8R	Strong	Biomarker	[10]
High blood pressure	DISY2OHH	Strong	Biomarker	[7]
Hypotrichosis 1	DIS0XPER	Strong	Autosomal dominant	[11]
Inherited bleeding disorder, platelet-type	DISIUNXT	Strong	Biomarker	[12]
leukaemia	DISS7D1V	Strong	Biomarker	[13]
Leukemia	DISNAKFL	Strong	Biomarker	[13]
Metabolic disorder	DIS71G5H	Strong	Altered Expression	[14]
Multiple sclerosis	DISB2WZI	Strong	Altered Expression	[15]
Obesity	DIS47Y1K	Strong	Biomarker	[14]
Small lymphocytic lymphoma	DIS30POX	moderate	Altered Expression	[16]
Hypotrichosis simplex	DIS8WHDJ	Supportive	Autosomal dominant	[11]
Bone osteosarcoma	DIST1004	Limited	Altered Expression	[17]
Glioblastoma multiforme	DISK8246	Limited	Biomarker	[18]
Melanoma	DIS1RRCY	Limited	Biomarker	[19]
Microphthalmia	DISGEBES	Limited	Biomarker	[19]
Neoplasm	DISZKGEW	Limited	Biomarker	[2]
Osteosarcoma	DISLQ7E2	Limited	Altered Expression	[17]
Stroke	DISX6UHX	Limited	Biomarker	[20]

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 APCDD1 (APCDD1).	[21]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene increases the methylation of Protein APCDD1 (APCDD1).	[30]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A decreases the methylation of Protein APCDD1 (APCDD1).	[32]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Tretinoin	DM49DUI	Approved	Tretinoin decreases the expression of Protein APCDD1 (APCDD1).	[22]
Doxorubicin	DMVP5YE	Approved	Doxorubicin affects the expression of Protein APCDD1 (APCDD1).	[23]
Cupric Sulfate	DMP0NFQ	Approved	Cupric Sulfate affects the expression of Protein APCDD1 (APCDD1).	[24]
Calcitriol	DM8ZVJ7	Approved	Calcitriol decreases the expression of Protein APCDD1 (APCDD1).	[25]
Carbamazepine	DMZOLBI	Approved	Carbamazepine affects the expression of Protein APCDD1 (APCDD1).	[26]
Progesterone	DMUY35B	Approved	Progesterone increases the expression of Protein APCDD1 (APCDD1).	[27]
Dexamethasone	DMMWZET	Approved	Dexamethasone increases the expression of Protein APCDD1 (APCDD1).	[28]
SNDX-275	DMH7W9X	Phase 3	SNDX-275 increases the expression of Protein APCDD1 (APCDD1).	[29]
PMID28460551-Compound-2	DM4DOUB	Patented	PMID28460551-Compound-2 decreases the expression of Protein APCDD1 (APCDD1).	[31]
Trichostatin A	DM9C8NX	Investigative	Trichostatin A increases the expression of Protein APCDD1 (APCDD1).	[33]
Sulforaphane	DMQY3L0	Investigative	Sulforaphane decreases the expression of Protein APCDD1 (APCDD1).	[34]

References

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• [9] Human hepatic 3D spheroids as a model for steatosis and insulin resistance.Sci Rep. 2018 Sep 24;8(1):14297. doi: 10.1038/s41598-018-32722-6.
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• [11] APCDD1 is a novel Wnt inhibitor mutated in hereditary hypotrichosis simplex. Nature. 2010 Apr 15;464(7291):1043-7. doi: 10.1038/nature08875.
• [12] Diagnostic high-throughput sequencing of 2396 patients with bleeding, thrombotic, and platelet disorders.Blood. 2019 Dec 5;134(23):2082-2091. doi: 10.1182/blood.2018891192.
• [13] Gene expression-based high-throughput screening(GE-HTS) and application to leukemia differentiation.Nat Genet. 2004 Mar;36(3):257-63. doi: 10.1038/ng1305. Epub 2004 Feb 8.
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• [16] Gene expression and splicing alterations analyzed by high throughput RNA sequencing of chronic lymphocytic leukemia specimens.BMC Cancer. 2015 Oct 16;15:714. doi: 10.1186/s12885-015-1708-9.
• [17] Epigenetic silencing of the Wnt antagonist APCDD1 by promoter DNA hyper-methylation contributes to osteosarcoma cell invasion and metastasis.Biochem Biophys Res Commun. 2017 Sep 9;491(1):91-97. doi: 10.1016/j.bbrc.2017.07.049. Epub 2017 Jul 8.
• [18] Improving the estimation of prognosis for glioblastoma patients by MR based hemodynamic tissue signatures.NMR Biomed. 2018 Dec;31(12):e4006. doi: 10.1002/nbm.4006. Epub 2018 Sep 21.
• [19] Development of an HTS-Compatible Assay for Discovery of Melanoma-Related Microphthalmia Transcription Factor Disruptors Using AlphaScreen Technology.SLAS Discov. 2017 Jan;22(1):58-66. doi: 10.1177/1087057116675274. Epub 2016 Nov 11.
• [20] Improving Community Stroke Preparedness in the HHS (Hip-Hop Stroke) Randomized Clinical Trial.Stroke. 2018 Apr;49(4):972-979. doi: 10.1161/STROKEAHA.117.019861.
• [21] 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.
• [22] 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.
• [23] 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.
• [24] Physiological and toxicological transcriptome changes in HepG2 cells exposed to copper. Physiol Genomics. 2009 Aug 7;38(3):386-401.
• [25] Large-scale in silico and microarray-based identification of direct 1,25-dihydroxyvitamin D3 target genes. Mol Endocrinol. 2005 Nov;19(11):2685-95.
• [26] Gene Expression Regulation and Pathway Analysis After Valproic Acid and Carbamazepine Exposure in a Human Embryonic Stem Cell-Based Neurodevelopmental Toxicity Assay. Toxicol Sci. 2015 Aug;146(2):311-20. doi: 10.1093/toxsci/kfv094. Epub 2015 May 15.
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• [29] 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.
• [30] 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.
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• [32] 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.
• [33] 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.
• [34] Transcriptome and DNA methylation changes modulated by sulforaphane induce cell cycle arrest, apoptosis, DNA damage, and suppression of proliferation in human liver cancer cells. Food Chem Toxicol. 2020 Feb;136:111047. doi: 10.1016/j.fct.2019.111047. Epub 2019 Dec 12.