Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OT6XY2JL)

• DOT Name: Lysyl oxidase homolog 4 (LOXL4)
• Synonyms: EC 1.4.3.13; Lysyl oxidase-like protein 4; Lysyl oxidase-related protein C
• Gene Name: LOXL4
• Related Disease:
  Advanced cancer
  Bladder cancer
  Breast carcinoma
  Breast neoplasm
  Carcinoma
  Carcinoma of liver and intrahepatic biliary tract
  Endometriosis
  Esophageal squamous cell carcinoma
  Head-neck squamous cell carcinoma
  Liver cancer
  Lung cancer
  Lung carcinoma
  Metastatic malignant neoplasm
  Squamous cell carcinoma
  Systemic sclerosis
  Triple negative breast cancer
  Urinary bladder cancer
  Urinary bladder neoplasm
  Gastric cancer
  Laryngeal squamous cell carcinoma
  Stomach cancer
  Melanoma
  Breast cancer
  Colorectal carcinoma
  Hepatocellular carcinoma
• UniProt ID: LOXL4_HUMAN
• EC Number: 1.4.3.13
• Pfam ID: PF01186 ; PF00530
• Sequence:
  MAWSPPATLFLFLLLLGQPPPSRPQSLGTTKLRLVGPESKPEEGRLEVLHQGQWGTVCDD
  NFAIQEATVACRQLGFEAALTWAHSAKYGQGEGPIWLDNVRCVGTESSLDQCGSNGWGVS
  DCSHSEDVGVICHPRRHRGYLSETVSNALGPQGRRLEEVRLKPILASAKQHSPVTEGAVE
  VKYEGHWRQVCDQGWTMNNSRVVCGMLGFPSEVPVDSHYYRKVWDLKMRDPKSRLKSLTN
  KNSFWIHQVTCLGTEPHMANCQVQVAPARGKLRPACPGGMHAVVSCVAGPHFRPPKTKPQ
  RKGSWAEEPRVRLRSGAQVGEGRVEVLMNRQWGTVCDHRWNLISASVVCRQLGFGSAREA
  LFGARLGQGLGPIHLSEVRCRGYERTLSDCPALEGSQNGCQHENDAAVRCNVPNMGFQNQ
  VRLAGGRIPEEGLLEVQVEVNGVPRWGSVCSENWGLTEAMVACRQLGLGFAIHAYKETWF
  WSGTPRAQEVVMSGVRCSGTELALQQCQRHGPVHCSHGGGRFLAGVSCMDSAPDLVMNAQ
  LVQETAYLEDRPLSQLYCAHEENCLSKSADHMDWPYGYRRLLRFSTQIYNLGRTDFRPKT
  GRDSWVWHQCHRHYHSIEVFTHYDLLTLNGSKVAEGHKASFCLEDTNCPTGLQRRYACAN
  FGEQGVTVGCWDTYRHDIDCQWVDITDVGPGNYIFQVIVNPHYEVAESDFSNNMLQCRCK
  YDGHRVWLHNCHTGNSYPANAELSLEQEQRLRNNLI
• Function: Catalyzes the oxidative deamination of lysine and hydroxylysine residues in collagen and elastin, resulting in the formation of covalent cross-linkages, and the stabilization of collagen and elastin fibers.
• Tissue Specificity: Expressed in many tissues, the highest levels among the tissues studied being in the skeletal muscle, testis and pancreas. Expressed in cartilage.
• Reactome Pathway:
  Crosslinking of collagen fibrils (R-HSA-2243919)
  Elastic fibre formation (R-HSA-1566948)

Molecular Interaction Atlas (MIA) of This DOT

25 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Advanced cancer	DISAT1Z9	Strong	Biomarker	[1]
Bladder cancer	DISUHNM0	Strong	Biomarker	[2]
Breast carcinoma	DIS2UE88	Strong	Altered Expression	[3]
Breast neoplasm	DISNGJLM	Strong	Altered Expression	[3]
Carcinoma	DISH9F1N	Strong	Altered Expression	[4]
Carcinoma of liver and intrahepatic biliary tract	DIS8WA0W	Strong	Altered Expression	[5]
Endometriosis	DISX1AG8	Strong	Genetic Variation	[6]
Esophageal squamous cell carcinoma	DIS5N2GV	Strong	Biomarker	[7]
Head-neck squamous cell carcinoma	DISF7P24	Strong	Altered Expression	[8]
Liver cancer	DISDE4BI	Strong	Altered Expression	[5]
Lung cancer	DISCM4YA	Strong	Biomarker	[9]
Lung carcinoma	DISTR26C	Strong	Biomarker	[9]
Metastatic malignant neoplasm	DIS86UK6	Strong	Biomarker	[1]
Squamous cell carcinoma	DISQVIFL	Strong	Altered Expression	[10]
Systemic sclerosis	DISF44L6	Strong	Biomarker	[11]
Triple negative breast cancer	DISAMG6N	Strong	Biomarker	[3]
Urinary bladder cancer	DISDV4T7	Strong	Biomarker	[2]
Urinary bladder neoplasm	DIS7HACE	Strong	Biomarker	[2]
Gastric cancer	DISXGOUK	moderate	Altered Expression	[12]
Laryngeal squamous cell carcinoma	DIS9UUVF	moderate	Altered Expression	[13]
Stomach cancer	DISKIJSX	moderate	Altered Expression	[12]
Melanoma	DIS1RRCY	Disputed	Biomarker	[14]
Breast cancer	DIS7DPX1	Limited	Altered Expression	[3]
Colorectal carcinoma	DIS5PYL0	Limited	Biomarker	[15]
Hepatocellular carcinoma	DIS0J828	Limited	Altered Expression	[1]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Valproate	DMCFE9I	Approved	Valproate decreases the expression of Lysyl oxidase homolog 4 (LOXL4).	[16]
Ciclosporin	DMAZJFX	Approved	Ciclosporin decreases the expression of Lysyl oxidase homolog 4 (LOXL4).	[17]
Doxorubicin	DMVP5YE	Approved	Doxorubicin decreases the expression of Lysyl oxidase homolog 4 (LOXL4).	[18]
Estradiol	DMUNTE3	Approved	Estradiol increases the expression of Lysyl oxidase homolog 4 (LOXL4).	[19]
Calcitriol	DM8ZVJ7	Approved	Calcitriol increases the expression of Lysyl oxidase homolog 4 (LOXL4).	[20]
Decitabine	DMQL8XJ	Approved	Decitabine increases the expression of Lysyl oxidase homolog 4 (LOXL4).	[21]
Progesterone	DMUY35B	Approved	Progesterone decreases the expression of Lysyl oxidase homolog 4 (LOXL4).	[22]
Cytarabine	DMZD5QR	Approved	Cytarabine decreases the expression of Lysyl oxidase homolog 4 (LOXL4).	[23]
Urethane	DM7NSI0	Phase 4	Urethane decreases the expression of Lysyl oxidase homolog 4 (LOXL4).	[24]
SNDX-275	DMH7W9X	Phase 3	SNDX-275 increases the expression of Lysyl oxidase homolog 4 (LOXL4).	[25]
PMID28460551-Compound-2	DM4DOUB	Patented	PMID28460551-Compound-2 decreases the expression of Lysyl oxidase homolog 4 (LOXL4).	[27]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene affects the methylation of Lysyl oxidase homolog 4 (LOXL4).	[26]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A decreases the methylation of Lysyl oxidase homolog 4 (LOXL4).	[28]

References

• [1] Exosome-mediated secretion of LOXL4 promotes hepatocellular carcinoma cell invasion and metastasis.Mol Cancer. 2019 Jan 31;18(1):18. doi: 10.1186/s12943-019-0948-8.
• [2] Lysyl oxidase family members in urological tumorigenesis and fibrosis.Oncotarget. 2018 Apr 13;9(28):20156-20164. doi: 10.18632/oncotarget.24948. eCollection 2018 Apr 13.
• [3] LOXL4 knockdown enhances tumor growth and lung metastasis through collagen-dependent extracellular matrix changes in triple-negative breast cancer.Oncotarget. 2017 Feb 14;8(7):11977-11989. doi: 10.18632/oncotarget.14450.
• [4] Characterisation of seven newly established head and neck squamous cell carcinoma cell lines.Eur Arch Otorhinolaryngol. 2015 May;272(5):1251-8. doi: 10.1007/s00405-014-3073-8. Epub 2014 May 4.
• [5] Derepression of LOXL4 inhibits liver cancer growth by reactivating compromised p53.Cell Death Differ. 2019 Nov;26(11):2237-2252. doi: 10.1038/s41418-019-0293-x. Epub 2019 Feb 6.
• [6] Single-nucleotide polymorphisms in the lysyl oxidase-like protein 4 and complement component 3 genes are associated with increased risk for endometriosis and endometriosis-associated infertility.Fertil Steril. 2011 Aug;96(2):512-5. doi: 10.1016/j.fertnstert.2011.06.001. Epub 2011 Jul 5.
• [7] Clinical significance of LOXL4 expression and features of LOXL4-associated protein-protein interaction network in esophageal squamous cell carcinoma.Amino Acids. 2019 May;51(5):813-828. doi: 10.1007/s00726-019-02723-4. Epub 2019 Mar 21.
• [8] Lysyl oxidase like-4 monoclonal antibody demonstrates therapeutic effect against head and neck squamous cell carcinoma cells and xenografts.Int J Cancer. 2016 May 15;138(10):2529-38. doi: 10.1002/ijc.29986. Epub 2016 Jan 25.
• [9] Downregulation of lysyl oxidase-like 4 LOXL4 by miR-135a-5p promotes lung cancer progression in vitro and in vivo.J Cell Physiol. 2019 Aug;234(10):18679-18687. doi: 10.1002/jcp.28508. Epub 2019 Apr 16.
• [10] LOXL4 as a selective molecular marker in primary and metastatic head/neck carcinoma.Anticancer Res. 2010 Nov;30(11):4567-71.
• [11] Systemic Sclerosis Dermal Fibroblasts Induce Cutaneous Fibrosis Through Lysyl Oxidase-like 4: New Evidence From Three-Dimensional Skin-like Tissues.Arthritis Rheumatol. 2020 May;72(5):791-801. doi: 10.1002/art.41163. Epub 2020 Apr 4.
• [12] Significance of the Lysyl Oxidase Members Lysyl Oxidase Like 1, 3, and 4 in Gastric Cancer.Digestion. 2018;98(4):238-248. doi: 10.1159/000489558. Epub 2018 Jul 25.
• [13] Differential expression of LOXL4 in normal and tumour tissue samples of laryngeal squamous cell carcinoma.Clin Otolaryngol. 2016 Jun;41(3):206-10. doi: 10.1111/coa.12498. Epub 2016 Feb 4.
• [14] Inhibition of the LOX enzyme family members with old and new ligands. Selectivity analysis revisited.Bioorg Med Chem Lett. 2018 Oct 1;28(18):3113-3118. doi: 10.1016/j.bmcl.2018.07.001. Epub 2018 Jul 6.
• [15] Differential expression of the LOX family genes in human colorectal adenocarcinomas.Oncol Rep. 2009 Oct;22(4):799-804. doi: 10.3892/or_00000502.
• [16] 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.
• [17] Integrative "-Omics" analysis in primary human hepatocytes unravels persistent mechanisms of cyclosporine A-induced cholestasis. Chem Res Toxicol. 2016 Dec 19;29(12):2164-2174.
• [18] Anthracycline inhibits recruitment of hypoxia-inducible transcription factors and suppresses tumor cell migration and cardiac angiogenic response in the host. J Biol Chem. 2012 Oct 12;287(42):34866-34882. doi: 10.1074/jbc.M112.374587. Epub 2012 Aug 20.
• [19] Effects of progesterone treatment on expression of genes involved in uterine quiescence. Reprod Sci. 2011 Aug;18(8):781-97.
• [20] Identification of vitamin D3 target genes in human breast cancer tissue. J Steroid Biochem Mol Biol. 2016 Nov;164:90-97.
• [21] Characterization of DOK1, a candidate tumor suppressor gene, in epithelial ovarian cancer. Mol Oncol. 2011 Oct;5(5):438-53. doi: 10.1016/j.molonc.2011.07.003. Epub 2011 Jul 26.
• [22] Unique transcriptome, pathways, and networks in the human endometrial fibroblast response to progesterone in endometriosis. Biol Reprod. 2011 Apr;84(4):801-15.
• [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] Ethyl carbamate induces cell death through its effects on multiple metabolic pathways. Chem Biol Interact. 2017 Nov 1;277:21-32.
• [25] 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.
• [26] 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.
• [27] 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.
• [28] 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.