Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTEUXA81)

• DOT Name: Histatin-3 (HTN3)
• Synonyms: Basic histidine-rich protein; Hst; Histatin 3; Hst 3; Histidine-rich protein 3; PB
• Gene Name: HTN3
• Related Disease:
  B-cell neoplasm
  Acinar cell carcinoma
  Acute leukaemia
  Breast cancer
  Breast carcinoma
  Carcinoma
  Colon cancer
  Colon carcinoma
  Cryptococcosis
  Gastric cancer
  Hepatocellular carcinoma
  High blood pressure
  leukaemia
  Leukemia
  Macular corneal dystrophy
  Myeloid leukaemia
  Oral candidiasis
  Stomach cancer
  Urinary bladder neoplasm
  Colorectal carcinoma
  Malaria
• UniProt ID: HIS3_HUMAN
• Sequence: MKFFVFALILALMLSMTGADSHAKRHHGYKRKFHEKHHSHRGYRSNYLYDN
• Function: Histatins are cationic and histidine-rich peptides mainly found in the saliva of higher primates. They are considered to be major precursors of the protective proteinaceous structure on tooth surfaces (enamel pellicle). Hsts can be divided into two major groups according to their biological functions: antimicrobial Hsts (e.g. Hst 5/HTN3) and cell-activating Hsts (e.g. Hst 1/HTN1, Hst 2/HTN1 and Hst 3/HTN3) ; [Histatin-3]: Histatin 3 (Hst 3) is mostly involved in cell migration and wound healing in the oral cavity. Also stimulates cell proliferation after binding to heat shock protein HSC70, which enhances HSC70-CDKN1B complex formation and subsequent ubiquitination during G1/S transition. Also displays antifungal activity against pathogenic yeast Candida albicans, however with less effectiveness than Hst 5 ; [His3-(20-43)-peptide]: Histatin 5 (Hst 5), a fragment of Hst 3, is the major histatin exhibiting antifungal and antibacterial activities. It is effective against pathogenic yeast C. albicans, C. neoformans, C. glabrata and S. cerevisiae as well as ESKAPE bacterial pathogens. Secreted Hst 5 mediates a multi-step intracellular mechanism of action against the pathogen. Depending on peptide concentration and pathogen, uptake across the membrane can occur through transporters, direct interaction with plasma membrane and/or receptor-mediated endocytosis. Binds C. albicans cell wall proteins SSA1 and SSA2 and glycans in an energy-independent manner, then is taken up by the cells through fungal polyamine transporters DUR3 and DUR31 in an energy-dependent manner. Internalized Hst5 is then targeted to the energized mitochondrion to induce reactive oxygen species (ROS) formation and subsequent release of intracellular non-lytic ATP which ultimately leads to fungal cell death. In addition, inhibits C. albicans TRK1 potassium-transporter which causes exudation of intracellular K(+), generating an osmotic imbalance leading to delayed membrane lysis and cell death. Also acts as a potent inhibitor of bacterial proteases such as Lys-gingipain and Arg-gingipain (rgpB) from P. gingivalis as well as human metalloproteases MMP2 and MMP9. The binding of metals such as zinc, copper or nickel with Hst 5 results in the protection of the enamel and antimicrobial activities such as the inhibition of microbial growth by decreasing the metal concentration, the formation of ROS commonly associated with redox-active metals, the induction of membrane disruption mediated by zinc binding. Also involved in coating oral surfaces in the form of a salivary film which reduces colonization by C. albicans on epithelial cell surfaces. Secreted Hst 5 can also internalize mammalian epithelial cells and target the mitochondria although it does not exert cytotoxic effects in these cells. In contrast with Hst 3, not able to promote wound healing in mammalian host cells.
• KEGG Pathway: Salivary secretion (hsa04970)
• Reactome Pathway: Antimicrobial peptides (R-HSA-6803157)

Molecular Interaction Atlas (MIA) of This DOT

21 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
B-cell neoplasm	DISVY326	Definitive	Genetic Variation	[1]
Acinar cell carcinoma	DIS37Y0J	Strong	Genetic Variation	[2]
Acute leukaemia	DISDQFDI	Strong	Genetic Variation	[3]
Breast cancer	DIS7DPX1	Strong	Biomarker	[4]
Breast carcinoma	DIS2UE88	Strong	Biomarker	[5]
Carcinoma	DISH9F1N	Strong	Biomarker	[6]
Colon cancer	DISVC52G	Strong	Altered Expression	[7]
Colon carcinoma	DISJYKUO	Strong	Altered Expression	[7]
Cryptococcosis	DISDYDTK	Strong	Biomarker	[8]
Gastric cancer	DISXGOUK	Strong	Biomarker	[9]
Hepatocellular carcinoma	DIS0J828	Strong	Genetic Variation	[10]
High blood pressure	DISY2OHH	Strong	Biomarker	[11]
leukaemia	DISS7D1V	Strong	Biomarker	[12]
Leukemia	DISNAKFL	Strong	Biomarker	[12]
Macular corneal dystrophy	DISOLD0H	Strong	Altered Expression	[13]
Myeloid leukaemia	DISMN944	Strong	Biomarker	[14]
Oral candidiasis	DISAVKAH	Strong	Altered Expression	[15]
Stomach cancer	DISKIJSX	Strong	Biomarker	[9]
Urinary bladder neoplasm	DIS7HACE	Strong	Biomarker	[4]
Colorectal carcinoma	DIS5PYL0	Limited	Genetic Variation	[16]
Malaria	DISQ9Y50	Limited	Genetic Variation	[17]

2 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 Histatin-3 (HTN3).	[18]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene decreases the methylation of Histatin-3 (HTN3).	[20]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Arsenic trioxide	DM61TA4	Approved	Arsenic trioxide increases the expression of Histatin-3 (HTN3).	[19]

References

• [1] Recognition DNA sequence of a novel putative transcription factor, BCL6.Biochem Biophys Res Commun. 1994 Oct 14;204(1):366-74. doi: 10.1006/bbrc.1994.2468.
• [2] The HTN3-MSANTD3 Fusion Gene Defines a Subset of Acinic Cell Carcinoma of the Salivary Gland.Am J Surg Pathol. 2019 Apr;43(4):489-496. doi: 10.1097/PAS.0000000000001200.
• [3] Genomic clone of hst with transforming activity from a patient with acute leukemia.Biochem Biophys Res Commun. 1987 Feb 13;142(3):1019-24. doi: 10.1016/0006-291x(87)91516-6.
• [4] Amplification of FGF-related genes in human tumors: possible involvement of HST in breast carcinomas.Oncogene. 1989 Jul;4(7):915-22.
• [5] A splice variant of HER2 corresponding to Herstatin is expressed in the noncancerous breast and in breast carcinomas.Neoplasia. 2008 Jul;10(7):687-96. doi: 10.1593/neo.08314.
• [6] D11S146 and BCL1 are physically linked but can be discriminated by their amplification status in human breast cancer.Genomics. 1991 Jun;10(2):410-6. doi: 10.1016/0888-7543(91)90326-a.
• [7] A transforming gene, hst, found in NIH 3T3 cells transformed with DNA from three stomach cancers and a colon cancer.Jpn J Cancer Res. 1987 Apr;78(4):325-8.
• [8] Discovery of a Membrane-Active, Ring-Modified Histidine Containing Ultrashort Amphiphilic Peptide That Exhibits Potent Inhibition of Cryptococcus neoformans.J Med Chem. 2017 Aug 10;60(15):6607-6621. doi: 10.1021/acs.jmedchem.7b00481. Epub 2017 Jul 25.
• [9] Cloned hst gene from normal human leukocyte DNA transforms NIH3T3 cells.Biochem Biophys Res Commun. 1988 Mar 30;151(3):965-72. doi: 10.1016/s0006-291x(88)80460-1.
• [10] Transforming genes in human hepatomas detected by a tumorigenicity assay.Jpn J Cancer Res. 1987 Oct;78(10):1036-40.
• [11] Low-dose sustained-release deoxycorticosterone acetate-induced hypertension in Bama miniature pigs for renal sympathetic nerve denervation.J Am Soc Hypertens. 2017 May;11(5):314-320. doi: 10.1016/j.jash.2017.02.006. Epub 2017 Mar 2.
• [12] Molecular cloning of six novel Krppel-like zinc finger genes from hematopoietic cells and identification of a novel transregulatory domain KRNB.J Biol Chem. 1999 Dec 10;274(50):35741-8. doi: 10.1074/jbc.274.50.35741.
• [13] Comparative differential proteomic analysis of minimal change disease and focal segmental glomerulosclerosis.BMC Nephrol. 2017 Feb 3;18(1):49. doi: 10.1186/s12882-017-0452-6.
• [14] His-1 and His-2: identification and chromosomal mapping of two commonly rearranged sites of viral integration in a myeloid leukemia.Oncogene. 1991 Nov;6(11):2041-7.
• [15] Effects of histatin 5 modifications on antifungal activity and kinetics of proteolysis.Protein Sci. 2020 Feb;29(2):480-493. doi: 10.1002/pro.3767. Epub 2019 Nov 20.
• [16] Amplification of the hst-1 gene in human esophageal carcinomas.Jpn J Cancer Res. 1988 May;79(5):584-8. doi: 10.1111/j.1349-7006.1988.tb00026.x.
• [17] An expanded histatin gene polymorphism and test of a possible disease resistant phenotype.Hum Mutat. 1997;10(1):58-64. doi: 10.1002/(SICI)1098-1004(1997)10:1<58::AID-HUMU8>3.0.CO;2-I.
• [18] 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.
• [19] Essential role of cell cycle regulatory genes p21 and p27 expression in inhibition of breast cancer cells by arsenic trioxide. Med Oncol. 2011 Dec;28(4):1225-54.
• [20] 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.