Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTPKV3UZ)

• DOT Name: Protein Hikeshi (HIKESHI)
• Gene Name: HIKESHI
• Related Disease:
  Gastric neoplasm
  Hereditary diffuse gastric adenocarcinoma
  Hypomyelinating leukodystrophy 13
  Melanoma
  Stomach cancer
  C11orf73-related autosomal recessive hypomyelinating leukodystrophy
  Clear cell renal carcinoma
  Movement disorder
  Gastric cancer
• UniProt ID: HIKES_HUMAN
• PDB ID: 3WVZ; 3WW0
• Pfam ID: PF21057 ; PF05603
• Sequence:
  MFGCLVAGRLVQTAAQQVAEDKFVFDLPDYESINHVVVFMLGTIPFPEGMGGSVYFSYPD
  SNGMPVWQLLGFVTNGKPSAIFKISGLKSGEGSQHPFGAMNIVRTPSVAQIGISVELLDS
  MAQQTPVGNAAVSSVDSFTQFTQKMLDNFYNFASSFAVSQAQMTPSPSEMFIPANVVLKW
  YENFQRRLAQNPLFWKT
• Function: Acts as a specific nuclear import carrier for HSP70 proteins following heat-shock stress: acts by mediating the nucleoporin-dependent translocation of ATP-bound HSP70 proteins into the nucleus. HSP70 proteins import is required to protect cells from heat shock damages. Does not translocate ADP-bound HSP70 proteins into the nucleus.
• Reactome Pathway: Regulation of HSF1-mediated heat shock response (R-HSA-3371453)

Molecular Interaction Atlas (MIA) of This DOT

9 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Gastric neoplasm	DISOKN4Y	Strong	Biomarker	[1]
Hereditary diffuse gastric adenocarcinoma	DISUIBYS	Strong	Biomarker	[1]
Hypomyelinating leukodystrophy 13	DIS6012E	Strong	Autosomal recessive	[2]
Melanoma	DIS1RRCY	Strong	Biomarker	[3]
Stomach cancer	DISKIJSX	Strong	Biomarker	[4]
C11orf73-related autosomal recessive hypomyelinating leukodystrophy	DISKC17T	Moderate	Autosomal recessive	[2]
Clear cell renal carcinoma	DISBXRFJ	moderate	Biomarker	[5]
Movement disorder	DISOJJ2D	moderate	Genetic Variation	[6]
Gastric cancer	DISXGOUK	Limited	Biomarker	[4]

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 Protein Hikeshi (HIKESHI).	[7]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A increases the methylation of Protein Hikeshi (HIKESHI).	[16]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Ciclosporin	DMAZJFX	Approved	Ciclosporin increases the expression of Protein Hikeshi (HIKESHI).	[8]
Tretinoin	DM49DUI	Approved	Tretinoin decreases the expression of Protein Hikeshi (HIKESHI).	[9]
Doxorubicin	DMVP5YE	Approved	Doxorubicin increases the expression of Protein Hikeshi (HIKESHI).	[10]
Cupric Sulfate	DMP0NFQ	Approved	Cupric Sulfate decreases the expression of Protein Hikeshi (HIKESHI).	[11]
Ivermectin	DMDBX5F	Approved	Ivermectin decreases the expression of Protein Hikeshi (HIKESHI).	[12]
Vorinostat	DMWMPD4	Approved	Vorinostat increases the expression of Protein Hikeshi (HIKESHI).	[13]
Testosterone	DM7HUNW	Approved	Testosterone decreases the expression of Protein Hikeshi (HIKESHI).	[14]
Diethylstilbestrol	DMN3UXQ	Approved	Diethylstilbestrol increases the expression of Protein Hikeshi (HIKESHI).	[15]
GALLICACID	DM6Y3A0	Investigative	GALLICACID increases the expression of Protein Hikeshi (HIKESHI).	[17]

References

• [1] A gene expression signature of acquired chemoresistance to cisplatin and fluorouracil combination chemotherapy in gastric cancer patients.PLoS One. 2011 Feb 18;6(2):e16694. doi: 10.1371/journal.pone.0016694.
• [2] Leukoencephalopathy and early death associated with an Ashkenazi-Jewish founder mutation in the Hikeshi gene. J Med Genet. 2016 Feb;53(2):132-7. doi: 10.1136/jmedgenet-2015-103232. Epub 2015 Nov 6.
• [3] Aggressiveness of human melanoma xenograft models is promoted by aneuploidy-driven gene expression deregulation.Oncotarget. 2012 Apr;3(4):399-413. doi: 10.18632/oncotarget.473.
• [4] Heat shock-induced HIKESHI protects cell viability via nuclear translocation of heat shock protein 70.Oncol Rep. 2017 Sep;38(3):1500-1506. doi: 10.3892/or.2017.5844. Epub 2017 Jul 21.
• [5] Gene expression-based biomarkers for discriminating early and late stage of clear cell renal cancer.Sci Rep. 2017 Mar 28;7:44997. doi: 10.1038/srep44997.
• [6] Absence of Hikeshi, a nuclear transporter for heat-shock protein HSP70, causes infantile hypomyelinating leukoencephalopathy.Eur J Hum Genet. 2017 Feb;25(3):366-370. doi: 10.1038/ejhg.2016.189. Epub 2016 Dec 21.
• [7] 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.
• [8] 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.
• [9] Development of a neural teratogenicity test based on human embryonic stem cells: response to retinoic acid exposure. Toxicol Sci. 2011 Dec;124(2):370-7.
• [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] Physiological and toxicological transcriptome changes in HepG2 cells exposed to copper. Physiol Genomics. 2009 Aug 7;38(3):386-401.
• [12] Quantitative proteomics reveals a broad-spectrum antiviral property of ivermectin, benefiting for COVID-19 treatment. J Cell Physiol. 2021 Apr;236(4):2959-2975. doi: 10.1002/jcp.30055. Epub 2020 Sep 22.
• [13] 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.
• [14] 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.
• [15] Identification of biomarkers and outcomes of endocrine disruption in human ovarian cortex using In Vitro Models. Toxicology. 2023 Feb;485:153425. doi: 10.1016/j.tox.2023.153425. Epub 2023 Jan 5.
• [16] 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.
• [17] Gene expression profile analysis of gallic acid-induced cell death process. Sci Rep. 2021 Aug 18;11(1):16743. doi: 10.1038/s41598-021-96174-1.