Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OT6IE3K2)

• DOT Name: Metastasis-suppressor KiSS-1 (KISS1)
• Synonyms: Kisspeptin-1
• Gene Name: KISS1
• Related Disease:
  Hypogonadotropic hypogonadism
  Hypogonadotropic hypogonadism 13 with or without anosmia
• UniProt ID: KISS1_HUMAN
• Pfam ID: PF15152
• Sequence:
  MNSLVSWQLLLFLCATHFGEPLEKVASVGNSRPTGQQLESLGLLAPGEQSLPCTERKPAA
  TARLSRRGTSLSPPPESSGSPQQPGLSAPHSRQIPAPQGAVLVQREKDLPNYNWNSFGLR
  FGKREAAPGNHGRSAGRG
• Function: Metastasis suppressor protein in malignant melanomas and in some breast cancers. May regulate events downstream of cell-matrix adhesion, perhaps involving cytoskeletal reorganization. Generates a C-terminally amidated peptide, metastin which functions as the endogenous ligand of the G-protein coupled receptor GPR54. Activation of the receptor inhibits cell proliferation and cell migration, key characteristics of tumor metastasis. Kp-10 is a decapeptide derived from the primary translation product, isolated in conditioned medium of first trimester trophoblast. Kp-10, but not other kisspeptins, increased intracellular Ca(2+) levels in isolated first trimester trophoblasts. Kp-10 is a paracrine/endocrine regulator in fine-tuning trophoblast invasion generated by the trophoblast itself. The receptor is also essential for normal gonadotropin-released hormone physiology and for puberty. The hypothalamic KiSS1/GPR54 system is a pivotal factor in central regulation of the gonadotropic axis at puberty and in adulthood.
• Tissue Specificity: Very high expression in placenta, with the next highest level in testis and moderate levels in pancreas, liver, small intestine and brain at much lower levels. Expression levels increased in both early placentas and molar pregnancies and are reduced in choriocarcinoma cells. Expressed at higher levels in first trimester trophoblasts than at term of gestation, but only expressed in the villous trophoblast.
• KEGG Pathway:
  Neuroactive ligand-receptor interaction (hsa04080)
  GnRH secretion (hsa04929)
• Reactome Pathway:
  G alpha (q) signalling events (R-HSA-416476)
  Peptide ligand-binding receptors (R-HSA-375276)

Molecular Interaction Atlas (MIA) of This DOT

2 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Hypogonadotropic hypogonadism	DIS8JSKR	Supportive	Autosomal dominant	[1]
Hypogonadotropic hypogonadism 13 with or without anosmia	DIS5R089	Limited	Autosomal recessive	[2]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Cisplatin	DMRHGI9	Approved	Metastasis-suppressor KiSS-1 (KISS1) increases the response to substance of Cisplatin.	[13]

9 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 Metastasis-suppressor KiSS-1 (KISS1).	[3]
Tretinoin	DM49DUI	Approved	Tretinoin increases the expression of Metastasis-suppressor KiSS-1 (KISS1).	[4]
Acetaminophen	DMUIE76	Approved	Acetaminophen decreases the expression of Metastasis-suppressor KiSS-1 (KISS1).	[5]
Hydrogen peroxide	DM1NG5W	Approved	Hydrogen peroxide increases the expression of Metastasis-suppressor KiSS-1 (KISS1).	[6]
Testosterone	DM7HUNW	Approved	Testosterone decreases the expression of Metastasis-suppressor KiSS-1 (KISS1).	[7]
Methotrexate	DM2TEOL	Approved	Methotrexate decreases the expression of Metastasis-suppressor KiSS-1 (KISS1).	[8]
Decitabine	DMQL8XJ	Approved	Decitabine increases the expression of Metastasis-suppressor KiSS-1 (KISS1).	[9]
Sevoflurane	DMC9O43	Approved	Sevoflurane decreases the expression of Metastasis-suppressor KiSS-1 (KISS1).	[10]
Formaldehyde	DM7Q6M0	Investigative	Formaldehyde decreases the expression of Metastasis-suppressor KiSS-1 (KISS1).	[12]

1 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 Metastasis-suppressor KiSS-1 (KISS1).	[11]

References

• [1] Inactivating KISS1 mutation and hypogonadotropic hypogonadism. N Engl J Med. 2012 Feb 16;366(7):629-35. doi: 10.1056/NEJMoa1111184.
• [2] Classification of Genes: Standardized Clinical Validity Assessment of Gene-Disease Associations Aids Diagnostic Exome Analysis and Reclassifications. Hum Mutat. 2017 May;38(5):600-608. doi: 10.1002/humu.23183. Epub 2017 Feb 13.
• [3] 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.
• [4] 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.
• [5] Multiple microRNAs function as self-protective modules in acetaminophen-induced hepatotoxicity in humans. Arch Toxicol. 2018 Feb;92(2):845-858.
• [6] Repression of Kisspeptin1 weakens hydrogen peroxide-caused injury in HTR8 cells via adjusting PI3K/AKT/mTOR pathway. J Biochem Mol Toxicol. 2020 May;34(5):e22461. doi: 10.1002/jbt.22461. Epub 2020 Feb 11.
• [7] The exosome-like vesicles derived from androgen exposed-prostate stromal cells promote epithelial cells proliferation and epithelial-mesenchymal transition. Toxicol Appl Pharmacol. 2021 Jan 15;411:115384. doi: 10.1016/j.taap.2020.115384. Epub 2020 Dec 25.
• [8] The contribution of methotrexate exposure and host factors on transcriptional variance in human liver. Toxicol Sci. 2007 Jun;97(2):582-94.
• [9] Chemical genomic screening for methylation-silenced genes in gastric cancer cell lines using 5-aza-2'-deoxycytidine treatment and oligonucleotide microarray. Cancer Sci. 2006 Jan;97(1):64-71.
• [10] The differential cancer growth associated with anaesthetics in a cancer xenograft model of mice: mechanisms and implications of postoperative cancer recurrence. Cell Biol Toxicol. 2023 Aug;39(4):1561-1575. doi: 10.1007/s10565-022-09747-9. Epub 2022 Aug 12.
• [11] 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.
• [12] Regulation of chromatin assembly and cell transformation by formaldehyde exposure in human cells. Environ Health Perspect. 2017 Sep 21;125(9):097019.
• [13] KiSS1 mediates platinum sensitivity and metastasis suppression in head and neck squamous cell carcinoma. Oncogene. 2011 Jul 14;30(28):3163-73. doi: 10.1038/onc.2011.39. Epub 2011 Mar 7.