Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTON6BFU)

• DOT Name: Opsin-3 (OPN3)
• Synonyms: Encephalopsin; Panopsin
• Gene Name: OPN3
• Related Disease:
  Allergic asthma
  Hepatocellular carcinoma
  Parkinson disease
  Asthma
  Small-cell lung cancer
  Lung adenocarcinoma
  Metastatic malignant neoplasm
  Leiomyomatosis
• UniProt ID: OPN3_HUMAN
• Pfam ID: PF00001
• Sequence:
  MYSGNRSGGHGYWDGGGAAGAEGPAPAGTLSPAPLFSPGTYERLALLLGSIGLLGVGNNL
  LVLVLYYKFQRLRTPTHLLLVNISLSDLLVSLFGVTFTFVSCLRNGWVWDTVGCVWDGFS
  GSLFGIVSIATLTVLAYERYIRVVHARVINFSWAWRAITYIWLYSLAWAGAPLLGWNRYI
  LDVHGLGCTVDWKSKDANDSSFVLFLFLGCLVVPLGVIAHCYGHILYSIRMLRCVEDLQT
  IQVIKILKYEKKLAKMCFLMIFTFLVCWMPYIVICFLVVNGHGHLVTPTISIVSYLFAKS
  NTVYNPVIYVFMIRKFRRSLLQLLCLRLLRCQRPAKDLPAAGSEMQIRPIVMSQKDGDRP
  KKKVTFNSSSIIFIITSDESLSVDDSDKTNGSKVDVIQVRPL
• Function: G-protein coupled receptor which selectively activates G proteins via ultraviolet A (UVA) light-mediated activation in the skin. Binds both 11-cis retinal and all-trans retinal. Regulates melanogenesis in melanocytes via inhibition of alpha-MSH-induced MC1R-mediated cAMP signaling, modulation of calcium flux, regulation of CAMK2 phosphorylation, and subsequently phosphorylation of CREB, p38, ERK and MITF in response to blue light. Plays a role in melanocyte survival through regulation of intracellular calcium levels and subsequent BCL2/RAF1 signaling. Additionally regulates apoptosis via cytochrome c release and subsequent activation of the caspase cascade. Required for TYR and DCT blue light-induced complex formation in melanocytes. Involved in keratinocyte differentiation in response to blue-light. Required for the UVA-mediated induction of calcium and mitogen-activated protein kinase signaling resulting in the expression of MMP1, MMP2, MMP3, MMP9 and TIMP1 in dermal fibroblasts. Plays a role in light-mediated glucose uptake, mitochondrial respiration and fatty acid metabolism in brown adipocyte tissues. May be involved in photorelaxation of airway smooth muscle cells, via blue-light dependent GPCR signaling pathways.
• Tissue Specificity: Expressed in tracheal airway smooth muscle (at protein level) . Expressed throughout the epidermis and dermis, predominantly in the basal layer on the facial and abdominal skin (at protein level) . Expressed in dermal fibroblasts (at protein level) . Expressed in melanocytes (at protein level) . Expressed in keratinocytes . Expressed in the retina .
• Reactome Pathway:
  Opsins (R-HSA-419771)
  G alpha (i) signalling events (R-HSA-418594)

Molecular Interaction Atlas (MIA) of This DOT

8 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Allergic asthma	DISHF0H3	Strong	Genetic Variation	[1]
Hepatocellular carcinoma	DIS0J828	Strong	Biomarker	[2]
Parkinson disease	DISQVHKL	Strong	Altered Expression	[3]
Asthma	DISW9QNS	moderate	Biomarker	[4]
Small-cell lung cancer	DISK3LZD	moderate	Genetic Variation	[5]
Lung adenocarcinoma	DISD51WR	Disputed	Altered Expression	[6]
Metastatic malignant neoplasm	DIS86UK6	Disputed	Altered Expression	[6]
Leiomyomatosis	DISNOOME	Limited	Genetic Variation	[7]

This DOT Affected the Drug Response of 1 Drug(s)

Drug Name	Drug ID	Highest Status	Interaction	REF
Cyclophosphamide	DM4O2Z7	Approved	Opsin-3 (OPN3) affects the response to substance of Cyclophosphamide.	[22]

1 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 Opsin-3 (OPN3).	[8]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Ciclosporin	DMAZJFX	Approved	Ciclosporin decreases the expression of Opsin-3 (OPN3).	[9]
Doxorubicin	DMVP5YE	Approved	Doxorubicin decreases the expression of Opsin-3 (OPN3).	[10]
Cisplatin	DMRHGI9	Approved	Cisplatin decreases the expression of Opsin-3 (OPN3).	[11]
Estradiol	DMUNTE3	Approved	Estradiol increases the expression of Opsin-3 (OPN3).	[12]
Arsenic trioxide	DM61TA4	Approved	Arsenic trioxide increases the expression of Opsin-3 (OPN3).	[13]
Progesterone	DMUY35B	Approved	Progesterone increases the expression of Opsin-3 (OPN3).	[14]
Niclosamide	DMJAGXQ	Approved	Niclosamide increases the expression of Opsin-3 (OPN3).	[15]
SNDX-275	DMH7W9X	Phase 3	SNDX-275 decreases the expression of Opsin-3 (OPN3).	[16]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene increases the expression of Opsin-3 (OPN3).	[9]
PMID28460551-Compound-2	DM4DOUB	Patented	PMID28460551-Compound-2 decreases the expression of Opsin-3 (OPN3).	[17]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A increases the expression of Opsin-3 (OPN3).	[18]
Trichostatin A	DM9C8NX	Investigative	Trichostatin A increases the expression of Opsin-3 (OPN3).	[19]
Formaldehyde	DM7Q6M0	Investigative	Formaldehyde decreases the expression of Opsin-3 (OPN3).	[20]
Sulforaphane	DMQY3L0	Investigative	Sulforaphane increases the expression of Opsin-3 (OPN3).	[21]

References

• [1] Identification of a novel asthma susceptibility gene on chromosome 1qter and its functional evaluation.Hum Mol Genet. 2008 Jul 1;17(13):1890-903. doi: 10.1093/hmg/ddn087. Epub 2008 Mar 15.
• [2] Opsin3 sensitizes hepatocellular carcinoma cells to 5-fluorouracil treatment by regulating the apoptotic pathway.Cancer Lett. 2012 Jul 1;320(1):96-103. doi: 10.1016/j.canlet.2012.01.035. Epub 2012 Feb 4.
• [3] Evidence for encephalopsin immunoreactivity in interneurones and striosomes of the monkey striatum.Exp Brain Res. 2018 Apr;236(4):955-961. doi: 10.1007/s00221-018-5191-9. Epub 2018 Jan 29.
• [4] Pathogenesis of allergic airway inflammation.Curr Allergy Asthma Rep. 2010 Jan;10(1):39-48. doi: 10.1007/s11882-009-0081-7.
• [5] Genetic association with overall survival of taxane-treated lung cancer patients - a genome-wide association study in human lymphoblastoid cell lines followed by a clinical association study.BMC Cancer. 2012 Sep 24;12:422. doi: 10.1186/1471-2407-12-422.
• [6] Expression of OPN3 in lung adenocarcinoma promotes epithelial-mesenchymal transition and tumor metastasis.Thorac Cancer. 2020 Feb;11(2):286-294. doi: 10.1111/1759-7714.13254. Epub 2019 Dec 5.
• [7] Germline deletions of EXO1 do not cause colorectal tumors and lesions which are null for EXO1 do not have microsatellite instability.Cancer Genet Cytogenet. 2003 Dec;147(2):121-7. doi: 10.1016/s0165-4608(03)00196-1.
• [8] 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.
• [9] Comparison of HepG2 and HepaRG by whole-genome gene expression analysis for the purpose of chemical hazard identification. Toxicol Sci. 2010 May;115(1):66-79.
• [10] 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.
• [11] Activation of AIFM2 enhances apoptosis of human lung cancer cells undergoing toxicological stress. Toxicol Lett. 2016 Sep 6;258:227-236.
• [12] 17-Estradiol Activates HSF1 via MAPK Signaling in ER-Positive Breast Cancer Cells. Cancers (Basel). 2019 Oct 11;11(10):1533. doi: 10.3390/cancers11101533.
• [13] Chronic occupational exposure to arsenic induces carcinogenic gene signaling networks and neoplastic transformation in human lung epithelial cells. Toxicol Appl Pharmacol. 2012 Jun 1;261(2):204-16.
• [14] Gene expression in endometrial cancer cells (Ishikawa) after short time high dose exposure to progesterone. Steroids. 2008 Jan;73(1):116-28.
• [15] Mitochondrial Uncoupling Induces Epigenome Remodeling and Promotes Differentiation in Neuroblastoma. Cancer Res. 2023 Jan 18;83(2):181-194. doi: 10.1158/0008-5472.CAN-22-1029.
• [16] 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.
• [17] 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.
• [18] Bisphenol A induces DSB-ATM-p53 signaling leading to cell cycle arrest, senescence, autophagy, stress response, and estrogen release in human fetal lung fibroblasts. Arch Toxicol. 2018 Apr;92(4):1453-1469.
• [19] 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.
• [20] Characterization of formaldehyde's genotoxic mode of action by gene expression analysis in TK6 cells. Arch Toxicol. 2013 Nov;87(11):1999-2012.
• [21] 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.
• [22] Gene expression profiling of 30 cancer cell lines predicts resistance towards 11 anticancer drugs at clinically achieved concentrations. Int J Cancer. 2006 Apr 1;118(7):1699-712. doi: 10.1002/ijc.21570.