Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTEHR7N7)

• DOT Name: Fibulin-2 (FBLN2)
• Synonyms: FIBL-2
• Gene Name: FBLN2
• Related Disease:
  Gastric cancer
  Stomach cancer
  Abdominal aortic aneurysm
  Arteriosclerosis
  Atherosclerosis
  Breast neoplasm
  Childhood acute lymphoblastic leukemia
  Colorectal carcinoma
  Depression
  Lung adenocarcinoma
  Lung cancer
  Lung carcinoma
  Pancreatic cancer
  Breast cancer
  Breast carcinoma
  High blood pressure
  Nasopharyngeal carcinoma
  Colorectal neoplasm
  Carcinoma
  Congenital heart disease
  Pulmonary arterial hypertension
• UniProt ID: FBLN2_HUMAN
• Pfam ID: PF01821 ; PF12662 ; PF07645 ; PF14670
• Sequence:
  MVLLWEPAGAWLALGLALALGPSVAAAAPRQDCTGVECPPLENCIEEALEPGACCATCVQ
  QGCACEGYQYYDCLQGGFVRGRVPAGQSYFVDFGSTECSCPPGGGKISCQFMLCPELPPN
  CIEAVVVADSCPQCGQVGCVHAGHKYAAGHTVHLPPCRACHCPDAGGELICYQLPGCHGN
  FSDAEEGDPERHYEDPYSYDQEVAEVEAATALGGEVQAGAVQAGAGGPPAALGGGSQPLS
  TIQAPPWPAVLPRPTAAAALGPPAPVQAKARRVTEDSEEEEEEEEEREEMAVTEQLAAGG
  HRGLDGLPTTAPAGPSLPIQEERAEAGARAEAGARPEENLILDAQATSRSTGPEGVTHAP
  SLGKAALVPTQAVPGSPRDPVKPSPHNILSTSLPDAAWIPPTREVPRKPQVLPHSHVEED
  TDPNSVHSIPRSSPEGSTKDLIETCCAAGQQWAIDNDECLEIPESGTEDNVCRTAQRHCC
  VSYLQEKSCMAGVLGAKEGETCGAEDNDSCGISLYKQCCDCCGLGLRVRAEGQSCESNPN
  LGYPCNHVMLSCCEGEEPLIVPEVRRPPEPAAAPRRVSEAEMAGREALSLGTEAELPNSL
  PGDDQDECLLLPGELCQHLCINTVGSYHCACFPGFSLQDDGRTCRPEGHPPQPEAPQEPA
  LKSEFSQVASNTIPLPLPQPNTCKDNGPCKQVCSTVGGSAICSCFPGYAIMADGVSCEDI
  NECVTDLHTCSRGEHCVNTLGSFHCYKALTCEPGYALKDGECEDVDECAMGTHTCQPGFL
  CQNTKGSFYCQARQRCMDGFLQDPEGNCVDINECTSLSEPCRPGFSCINTVGSYTCQRNP
  LICARGYHASDDGTKCVDVNECETGVHRCGEGQVCHNLPGSYRCDCKAGFQRDAFGRGCI
  DVNECWASPGRLCQHTCENTLGSYRCSCASGFLLAADGKRCEDVNECEAQRCSQECANIY
  GSYQCYCRQGYQLAEDGHTCTDIDECAQGAGILCTFRCLNVPGSYQCACPEQGYTMTANG
  RSCKDVDECALGTHNCSEAETCHNIQGSFRCLRFECPPNYVQVSKTKCERTTCHDFLECQ
  NSPARITHYQLNFQTGLLVPAHIFRIGPAPAFTGDTIALNIIKGNEEGYFGTRRLNAYTG
  VVYLQRAVLEPRDFALDVEMKLWRQGSVTTFLAKMHIFFTTFAL
• Function: Its binding to fibronectin and some other ligands is calcium dependent. May act as an adapter that mediates the interaction between FBN1 and ELN.
• Tissue Specificity: Component of both basement membranes and other connective tissues. Expressed in heart, placenta and ovary.
• KEGG Pathway: Cytoskeleton in muscle cells (hsa04820)
• Reactome Pathway: Molecules associated with elastic fibres (R-HSA-2129379)

Molecular Interaction Atlas (MIA) of This DOT

21 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Gastric cancer	DISXGOUK	Definitive	Altered Expression	[1]
Stomach cancer	DISKIJSX	Definitive	Altered Expression	[1]
Abdominal aortic aneurysm	DISD06OF	Strong	Biomarker	[2]
Arteriosclerosis	DISK5QGC	Strong	Biomarker	[3]
Atherosclerosis	DISMN9J3	Strong	Biomarker	[3]
Breast neoplasm	DISNGJLM	Strong	Biomarker	[4]
Childhood acute lymphoblastic leukemia	DISJ5D6U	Strong	Posttranslational Modification	[5]
Colorectal carcinoma	DIS5PYL0	Strong	Altered Expression	[6]
Depression	DIS3XJ69	Strong	Biomarker	[7]
Lung adenocarcinoma	DISD51WR	Strong	Biomarker	[8]
Lung cancer	DISCM4YA	Strong	Biomarker	[9]
Lung carcinoma	DISTR26C	Strong	Biomarker	[9]
Pancreatic cancer	DISJC981	Strong	Biomarker	[10]
Breast cancer	DIS7DPX1	moderate	Altered Expression	[11]
Breast carcinoma	DIS2UE88	moderate	Altered Expression	[11]
High blood pressure	DISY2OHH	moderate	Biomarker	[12]
Nasopharyngeal carcinoma	DISAOTQ0	moderate	Biomarker	[13]
Colorectal neoplasm	DISR1UCN	Disputed	Biomarker	[14]
Carcinoma	DISH9F1N	Limited	Biomarker	[15]
Congenital heart disease	DISQBA23	Limited	Autosomal dominant	[16]
Pulmonary arterial hypertension	DISP8ZX5	Limited	Autosomal dominant	[16]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Valproate	DMCFE9I	Approved	Valproate increases the expression of Fibulin-2 (FBLN2).	[17]
Doxorubicin	DMVP5YE	Approved	Doxorubicin increases the expression of Fibulin-2 (FBLN2).	[18]
Cisplatin	DMRHGI9	Approved	Cisplatin affects the expression of Fibulin-2 (FBLN2).	[19]
Quercetin	DM3NC4M	Approved	Quercetin increases the expression of Fibulin-2 (FBLN2).	[21]
Triclosan	DMZUR4N	Approved	Triclosan decreases the expression of Fibulin-2 (FBLN2).	[22]
Carbamazepine	DMZOLBI	Approved	Carbamazepine affects the expression of Fibulin-2 (FBLN2).	[23]
Decitabine	DMQL8XJ	Approved	Decitabine affects the expression of Fibulin-2 (FBLN2).	[19]
Progesterone	DMUY35B	Approved	Progesterone increases the expression of Fibulin-2 (FBLN2).	[24]
Permethrin	DMZ0Q1G	Approved	Permethrin increases the expression of Fibulin-2 (FBLN2).	[25]
SNDX-275	DMH7W9X	Phase 3	SNDX-275 increases the expression of Fibulin-2 (FBLN2).	[26]
Belinostat	DM6OC53	Phase 2	Belinostat decreases the expression of Fibulin-2 (FBLN2).	[27]
PMID28460551-Compound-2	DM4DOUB	Patented	PMID28460551-Compound-2 increases the expression of Fibulin-2 (FBLN2).	[29]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A increases the expression of Fibulin-2 (FBLN2).	[30]
Trichostatin A	DM9C8NX	Investigative	Trichostatin A increases the expression of Fibulin-2 (FBLN2).	[31]
Acetaldehyde	DMJFKG4	Investigative	Acetaldehyde increases the expression of Fibulin-2 (FBLN2).	[32]

2 Drug(s) Affected the Post-Translational Modifications of This DOT

Drug Name	Drug ID	Highest Status	Interaction	REF
Arsenic	DMTL2Y1	Approved	Arsenic affects the methylation of Fibulin-2 (FBLN2).	[20]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene increases the methylation of Fibulin-2 (FBLN2).	[28]

References

• [1] Fibulin-2 inhibits development of gastric cancer by downregulating -catenin.Oncol Lett. 2019 Sep;18(3):2799-2804. doi: 10.3892/ol.2019.10599. Epub 2019 Jul 10.
• [2] Fibulin-2 exhibits high degree of variability, but no structural changes concordant with abdominal aortic aneurysms.Eur J Hum Genet. 1998 Nov-Dec;6(6):642-6. doi: 10.1038/sj.ejhg.5200245.
• [3] Analysis of gene expression profile identifies potential biomarkers for atherosclerosis.Mol Med Rep. 2016 Oct;14(4):3052-8. doi: 10.3892/mmr.2016.5650. Epub 2016 Aug 19.
• [4] Cleavage of Fibulin-2 by the aggrecanases ADAMTS-4 and ADAMTS-5 contributes to the tumorigenic potential of breast cancer cells.Oncotarget. 2017 Feb 21;8(8):13716-13729. doi: 10.18632/oncotarget.14627.
• [5] Epigenetic analysis of childhood acute lymphoblastic leukemia.Epigenetics. 2009 Apr 1;4(3):185-93. doi: 10.4161/epi.4.3.8752. Epub 2009 Apr 12.
• [6] Identification of novel methylated targets in colorectal cancer by microarray analysis and construction of co-expression network.Oncol Lett. 2017 Sep;14(3):2643-2648. doi: 10.3892/ol.2017.6506. Epub 2017 Jun 30.
• [7] Up-regulated miR-192-5p expression rescues cognitive impairment and restores neural function in mice with depression via the Fbln2-mediated TGF-1 signaling pathway.FASEB J. 2019 Jan;33(1):606-618. doi: 10.1096/fj.201800210RR. Epub 2018 Aug 17.
• [8] Fibulin-2 is a driver of malignant progression in lung adenocarcinoma.PLoS One. 2013 Jun 10;8(6):e67054. doi: 10.1371/journal.pone.0067054. Print 2013.
• [9] The expression level of fibulin-2 in the circulating RNA (ctRNA) of epithelial tumor cells of peripheral blood and tumor tissue of patients with metastatic lung cancer.Mol Biol Rep. 2019 Aug;46(4):4001-4008. doi: 10.1007/s11033-019-04846-z. Epub 2019 May 8.
• [10] Role of MUC4-NIDO domain in the MUC4-mediated metastasis of pancreatic cancer cells.Oncogene. 2012 Jul 12;31(28):3346-56. doi: 10.1038/onc.2011.505. Epub 2011 Nov 21.
• [11] Fibulin-2 is required for basement membrane integrity of mammary epithelium.Sci Rep. 2018 Sep 20;8(1):14139. doi: 10.1038/s41598-018-32507-x.
• [12] Two variants in the fibulin2 gene are associated with lower systolic blood pressure and decreased risk of hypertension.PLoS One. 2012;7(8):e43051. doi: 10.1371/journal.pone.0043051. Epub 2012 Aug 13.
• [13] Anti-angiogenic and tumor-suppressive roles of candidate tumor-suppressor gene, Fibulin-2, in nasopharyngeal carcinoma.Oncogene. 2012 Feb 9;31(6):728-38. doi: 10.1038/onc.2011.272. Epub 2011 Jul 11.
• [14] Comparing the DNA hypermethylome with gene mutations in human colorectal cancer.PLoS Genet. 2007 Sep;3(9):1709-23. doi: 10.1371/journal.pgen.0030157. Epub 2007 Jul 31.
• [15] Interaction between the ADAMTS-12 metalloprotease and fibulin-2 induces tumor-suppressive effects in breast cancer cells.Oncotarget. 2014 Mar 15;5(5):1253-64. doi: 10.18632/oncotarget.1690.
• [16] Technical standards for the interpretation and reporting of constitutional copy-number variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics (ACMG) and the Clinical Genome Resource (ClinGen). Genet Med. 2020 Feb;22(2):245-257. doi: 10.1038/s41436-019-0686-8. Epub 2019 Nov 6.
• [17] Human embryonic stem cell-derived test systems for developmental neurotoxicity: a transcriptomics approach. Arch Toxicol. 2013 Jan;87(1):123-43.
• [18] RNA sequence analysis of inducible pluripotent stem cell-derived cardiomyocytes reveals altered expression of DNA damage and cell cycle genes in response to doxorubicin. Toxicol Appl Pharmacol. 2018 Oct 1;356:44-53.
• [19] Acute hypersensitivity of pluripotent testicular cancer-derived embryonal carcinoma to low-dose 5-aza deoxycytidine is associated with global DNA Damage-associated p53 activation, anti-pluripotency and DNA demethylation. PLoS One. 2012;7(12):e53003. doi: 10.1371/journal.pone.0053003. Epub 2012 Dec 27.
• [20] 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.
• [21] Integrated assessment by multiple gene expression analysis of quercetin bioactivity on anticancer-related mechanisms in colon cancer cells in vitro. Eur J Nutr. 2005 Mar;44(3):143-56. doi: 10.1007/s00394-004-0503-1. Epub 2004 Apr 30.
• [22] Transcriptome and DNA methylome dynamics during triclosan-induced cardiomyocyte differentiation toxicity. Stem Cells Int. 2018 Oct 29;2018:8608327.
• [23] 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.
• [24] Progesterone regulation of implantation-related genes: new insights into the role of oestrogen. Cell Mol Life Sci. 2007 Apr;64(7-8):1009-32.
• [25] Exposure to Insecticides Modifies Gene Expression and DNA Methylation in Hematopoietic Tissues In Vitro. Int J Mol Sci. 2023 Mar 26;24(7):6259. doi: 10.3390/ijms24076259.
• [26] 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.
• [27] 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.
• [28] 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.
• [29] 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.
• [30] Alternatives for the worse: Molecular insights into adverse effects of bisphenol a and substitutes during human adipocyte differentiation. Environ Int. 2021 Nov;156:106730. doi: 10.1016/j.envint.2021.106730. Epub 2021 Jun 27.
• [31] 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.
• [32] Transcriptome profile analysis of saturated aliphatic aldehydes reveals carbon number-specific molecules involved in pulmonary toxicity. Chem Res Toxicol. 2014 Aug 18;27(8):1362-70.