Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTK1EQ49)

• DOT Name: SPARC-related modular calcium-binding protein 2 (SMOC2)
• Synonyms: Secreted modular calcium-binding protein 2; SMOC-2; Smooth muscle-associated protein 2; SMAP-2
• Gene Name: SMOC2
• Related Disease:
  Autoimmune disease
  Colon cancer
  Colon carcinoma
  Dentin dysplasia type I
  Endometrial cancer
  Endometrial carcinoma
  Endometriosis
  Fatty liver disease
  Hepatitis C virus infection
  Hepatocellular carcinoma
  Metabolic disorder
  Neoplasm
  Non-alcoholic fatty liver disease
  Pulmonary fibrosis
  Renal fibrosis
  Tooth agenesis
  Colorectal carcinoma
  Metastatic malignant neoplasm
  Atypical dentin dysplasia due to SMOC2 deficiency
  Lymphoma
  Vitiligo
• UniProt ID: SMOC2_HUMAN
• Pfam ID: PF07648 ; PF10591 ; PF16597 ; PF00086
• Sequence:
  MLLPQLCWLPLLAGLLPPVPAQKFSALTFLRVDQDKDKDCSLDCAGSPQKPLCASDGRTF
  LSRCEFQRAKCKDPQLEIAYRGNCKDVSRCVAERKYTQEQARKEFQQVFIPECNDDGTYS
  QVQCHSYTGYCWCVTPNGRPISGTAVAHKTPRCPGSVNEKLPQREGTGKTDDAAAPALET
  QPQGDEEDIASRYPTLWTEQVKSRQNKTNKNSVSSCDQEHQSALEEAKQPKNDNVVIPEC
  AHGGLYKPVQCHPSTGYCWCVLVDTGRPIPGTSTRYEQPKCDNTARAHPAKARDLYKGRQ
  LQGCPGAKKHEFLTSVLDALSTDMVHAASDPSSSSGRLSEPDPSHTLEERVVHWYFKLLD
  KNSSGDIGKKEIKPFKRFLRKKSKPKKCVKKFVEYCDVNNDKSISVQELMGCLGVAKEDG
  KADTKKRHTPRGHAESTSNRQPRKQG
• Function: Promotes matrix assembly and cell adhesiveness. Can stimulate endothelial cell proliferation, migration, as well as angiogenesis.

Molecular Interaction Atlas (MIA) of This DOT

21 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Autoimmune disease	DISORMTM	Strong	Biomarker	[1]
Colon cancer	DISVC52G	Strong	Biomarker	[2]
Colon carcinoma	DISJYKUO	Strong	Biomarker	[2]
Dentin dysplasia type I	DISS0DLW	Strong	Autosomal recessive	[3]
Endometrial cancer	DISW0LMR	Strong	Altered Expression	[4]
Endometrial carcinoma	DISXR5CY	Strong	Altered Expression	[4]
Endometriosis	DISX1AG8	Strong	Altered Expression	[5]
Fatty liver disease	DIS485QZ	Strong	Altered Expression	[6]
Hepatitis C virus infection	DISQ0M8R	Strong	Biomarker	[7]
Hepatocellular carcinoma	DIS0J828	Strong	Biomarker	[8]
Metabolic disorder	DIS71G5H	Strong	Biomarker	[6]
Neoplasm	DISZKGEW	Strong	Biomarker	[8]
Non-alcoholic fatty liver disease	DISDG1NL	Strong	Biomarker	[6]
Pulmonary fibrosis	DISQKVLA	Strong	Biomarker	[9]
Renal fibrosis	DISMHI3I	Strong	Altered Expression	[10]
Tooth agenesis	DIS1PWC7	Strong	Genetic Variation	[11]
Colorectal carcinoma	DIS5PYL0	moderate	Genetic Variation	[12]
Metastatic malignant neoplasm	DIS86UK6	moderate	Biomarker	[8]
Atypical dentin dysplasia due to SMOC2 deficiency	DISCXF9N	Supportive	Autosomal recessive	[3]
Lymphoma	DISN6V4S	Limited	Biomarker	[13]
Vitiligo	DISR05SL	Limited	Biomarker	[1]

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 SPARC-related modular calcium-binding protein 2 (SMOC2).	[14]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene decreases the methylation of SPARC-related modular calcium-binding protein 2 (SMOC2).	[25]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Tretinoin	DM49DUI	Approved	Tretinoin increases the expression of SPARC-related modular calcium-binding protein 2 (SMOC2).	[15]
Doxorubicin	DMVP5YE	Approved	Doxorubicin decreases the expression of SPARC-related modular calcium-binding protein 2 (SMOC2).	[16]
Cupric Sulfate	DMP0NFQ	Approved	Cupric Sulfate increases the expression of SPARC-related modular calcium-binding protein 2 (SMOC2).	[17]
Estradiol	DMUNTE3	Approved	Estradiol increases the expression of SPARC-related modular calcium-binding protein 2 (SMOC2).	[18]
Hydrogen peroxide	DM1NG5W	Approved	Hydrogen peroxide affects the expression of SPARC-related modular calcium-binding protein 2 (SMOC2).	[19]
Vorinostat	DMWMPD4	Approved	Vorinostat decreases the expression of SPARC-related modular calcium-binding protein 2 (SMOC2).	[20]
Zoledronate	DMIXC7G	Approved	Zoledronate increases the expression of SPARC-related modular calcium-binding protein 2 (SMOC2).	[21]
Menadione	DMSJDTY	Approved	Menadione affects the expression of SPARC-related modular calcium-binding protein 2 (SMOC2).	[19]
Dexamethasone	DMMWZET	Approved	Dexamethasone increases the expression of SPARC-related modular calcium-binding protein 2 (SMOC2).	[22]
Cytarabine	DMZD5QR	Approved	Cytarabine decreases the expression of SPARC-related modular calcium-binding protein 2 (SMOC2).	[23]
SNDX-275	DMH7W9X	Phase 3	SNDX-275 increases the expression of SPARC-related modular calcium-binding protein 2 (SMOC2).	[24]
Trichostatin A	DM9C8NX	Investigative	Trichostatin A increases the expression of SPARC-related modular calcium-binding protein 2 (SMOC2).	[26]
Formaldehyde	DM7Q6M0	Investigative	Formaldehyde increases the expression of SPARC-related modular calcium-binding protein 2 (SMOC2).	[27]

References

• [1] Variants in PTPN22 and SMOC2 genes and the risk of thyroid disease in the Jordanian Arab population.Endocrine. 2013 Dec;44(3):702-9. doi: 10.1007/s12020-013-9908-z. Epub 2013 Mar 6.
• [2] Induction of the intestinal stem cell signature gene SMOC-2 is required for L1-mediated colon cancer progression.Oncogene. 2016 Feb 4;35(5):549-57. doi: 10.1038/onc.2015.127. Epub 2015 Apr 27.
• [3] Homozygosity mapping and candidate prioritization identify mutations, missed by whole-exome sequencing, in SMOC2, causing major dental developmental defects. Am J Hum Genet. 2011 Dec 9;89(6):773-81. doi: 10.1016/j.ajhg.2011.11.002.
• [4] Targeting cancer stem cell signature gene SMOC-2 Overcomes chemoresistance and inhibits cell proliferation of endometrial carcinoma.EBioMedicine. 2019 Feb;40:276-289. doi: 10.1016/j.ebiom.2018.12.044. Epub 2018 Dec 26.
• [5] Increased expression of ID2, PRELP and SMOC2 genes in patients with endometriosis.Braz J Med Biol Res. 2017 Jul 3;50(7):e5782. doi: 10.1590/1414-431X20175782.
• [6] Secreted modular calcium-binding protein 2 promotes high fat diet (HFD)-induced hepatic steatosis through enhancing lipid deposition, fibrosis and inflammation via targeting TGF-1.Biochem Biophys Res Commun. 2019 Jan 29;509(1):48-55. doi: 10.1016/j.bbrc.2018.12.006. Epub 2018 Dec 20.
• [7] Genome-wide transcriptome analysis identifies novel gene signatures implicated in human chronic liver disease.Am J Physiol Gastrointest Liver Physiol. 2013 Sep 1;305(5):G364-74. doi: 10.1152/ajpgi.00077.2013. Epub 2013 Jun 27.
• [8] Overexpression of SMOC2 Attenuates the Tumorigenicity of Hepatocellular Carcinoma Cells and Is Associated With a Positive Postoperative Prognosis in Human Hepatocellular Carcinoma.J Cancer. 2017 Oct 17;8(18):3812-3827. doi: 10.7150/jca.20775. eCollection 2017.
• [9] Suppression of SMOC2 reduces bleomycin (BLM)-induced pulmonary fibrosis by inhibition of TGF-1/SMADs pathway.Biomed Pharmacother. 2018 Sep;105:841-847. doi: 10.1016/j.biopha.2018.03.058. Epub 2018 Jun 18.
• [10] Silencing SMOC2 ameliorates kidney fibrosis by inhibiting fibroblast to myofibroblast transformation.JCI Insight. 2017 Apr 20;2(8):e90299. doi: 10.1172/jci.insight.90299. eCollection 2017 Apr 20.
• [11] Recessive oligodontia linked to a homozygous loss-of-function mutation in the SMOC2 gene.Arch Oral Biol. 2013 May;58(5):462-6. doi: 10.1016/j.archoralbio.2012.12.008. Epub 2013 Jan 11.
• [12] Identification, isolation and characterization of human LGR5-positive colon adenoma cells.Development. 2018 Mar 14;145(6):dev153049. doi: 10.1242/dev.153049.
• [13] Evolving Strategies for the Treatment of T-Cell Lymphoma: A Systematic Review and Recent Patents.Recent Pat Anticancer Drug Discov. 2018;13(3):308-340. doi: 10.2174/1574892813666180517102801.
• [14] 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.
• [15] 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.
• [16] 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.
• [17] Physiological and toxicological transcriptome changes in HepG2 cells exposed to copper. Physiol Genomics. 2009 Aug 7;38(3):386-401.
• [18] Epidermal growth factor receptor signalling in human breast cancer cells operates parallel to estrogen receptor alpha signalling and results in tamoxifen insensitive proliferation. BMC Cancer. 2014 Apr 23;14:283.
• [19] 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.
• [20] 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.
• [21] Interleukin-19 as a translational indicator of renal injury. Arch Toxicol. 2015 Jan;89(1):101-6.
• [22] Identification of mechanisms of action of bisphenol a-induced human preadipocyte differentiation by transcriptional profiling. Obesity (Silver Spring). 2014 Nov;22(11):2333-43.
• [23] Cytosine arabinoside induces ectoderm and inhibits mesoderm expression in human embryonic stem cells during multilineage differentiation. Br J Pharmacol. 2011 Apr;162(8):1743-56.
• [24] A transcriptome-based classifier to identify developmental toxicants by stem cell testing: design, validation and optimization for histone deacetylase inhibitors. Arch Toxicol. 2015 Sep;89(9):1599-618.
• [25] 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.
• [26] 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.
• [27] Cystathionine metabolic enzymes play a role in the inflammation resolution of human keratinocytes in response to sub-cytotoxic formaldehyde exposure. Toxicol Appl Pharmacol. 2016 Nov 1;310:185-194.