Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTSFEZ2O)

• DOT Name: IST1 homolog (IST1)
• Synonyms: hIST1; Charged multivesicular body protein 8; CHMP8; Putative MAPK-activating protein PM28
• Gene Name: IST1
• Related Disease:
  Acute myelogenous leukaemia
  Breast cancer
  Breast carcinoma
  Carcinoma of esophagus
  Esophageal cancer
  Esophageal squamous cell carcinoma
  Gastric adenocarcinoma
  Lung cancer
  Lung carcinoma
  Lung neoplasm
  Neoplasm of esophagus
  Squamous cell carcinoma
  Neoplasm
• UniProt ID: IST1_HUMAN
• PDB ID: 3FRR; 3FRS; 3JC1; 4U7E; 4U7I; 4U7Y; 4WZX; 6E8G; 6TZ4; 6TZ5; 6TZA; 7S7J; 8UC6
• Pfam ID: PF03398
• Sequence:
  MLGSGFKAERLRVNLRLVINRLKLLEKKKTELAQKARKEIADYLAAGKDERARIRVEHII
  REDYLVEAMEILELYCDLLLARFGLIQSMKELDSGLAESVSTLIWAAPRLQSEVAELKIV
  ADQLCAKYSKEYGKLCRTNQIGTVNDRLMHKLSVEAPPKILVERYLIEIAKNYNVPYEPD
  SVVMAEAPPGVETDLIDVGFTDDVKKGGPGRGGSGGFTAPVGGPDGTVPMPMPMPMPSAN
  TPFSYPLPKGPSDFNGLPMGTYQAFPNIHPPQIPATPPSYESVDDINADKNISSAQIVGP
  GPKPEASAKLPSRPADNYDNFVLPELPSVPDTLPTASAGASTSASEDIDFDDLSRRFEEL
  KKKT
• Function: ESCRT-III-like protein involved in cytokinesis, nuclear envelope reassembly and endosomal tubulation. Is required for efficient abscission during cytokinesis. Involved in recruiting VPS4A and/or VPS4B to the midbody of dividing cells. During late anaphase, involved in nuclear envelope reassembly and mitotic spindle disassembly together with the ESCRT-III complex: IST1 acts by mediating the recruitment of SPAST to the nuclear membrane, leading to microtubule severing. Recruited to the reforming nuclear envelope (NE) during anaphase by LEMD2. Regulates early endosomal tubulation together with the ESCRT-III complex by mediating the recruitment of SPAST.
• KEGG Pathway: Endocytosis (hsa04144)
• Reactome Pathway:
  Sealing of the nuclear envelope (NE) by ESCRT-III (R-HSA-9668328)
  Neutrophil degranulation (R-HSA-6798695)

Molecular Interaction Atlas (MIA) of This DOT

13 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Acute myelogenous leukaemia	DISCSPTN	Strong	Genetic Variation	[1]
Breast cancer	DIS7DPX1	Strong	Altered Expression	[2]
Breast carcinoma	DIS2UE88	Strong	Genetic Variation	[3]
Carcinoma of esophagus	DISS6G4D	Strong	Biomarker	[4]
Esophageal cancer	DISGB2VN	Strong	Biomarker	[4]
Esophageal squamous cell carcinoma	DIS5N2GV	Strong	Altered Expression	[5]
Gastric adenocarcinoma	DISWWLTC	Strong	Biomarker	[6]
Lung cancer	DISCM4YA	Strong	Altered Expression	[4]
Lung carcinoma	DISTR26C	Strong	Altered Expression	[4]
Lung neoplasm	DISVARNB	Strong	Altered Expression	[7]
Neoplasm of esophagus	DISOLKAQ	Strong	Biomarker	[4]
Squamous cell carcinoma	DISQVIFL	Strong	Altered Expression	[7]
Neoplasm	DISZKGEW	Limited	Altered Expression	[4]

8 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 IST1 homolog (IST1).	[8]
Tretinoin	DM49DUI	Approved	Tretinoin increases the expression of IST1 homolog (IST1).	[9]
Doxorubicin	DMVP5YE	Approved	Doxorubicin increases the expression of IST1 homolog (IST1).	[10]
Ivermectin	DMDBX5F	Approved	Ivermectin decreases the expression of IST1 homolog (IST1).	[11]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A decreases the expression of IST1 homolog (IST1).	[12]
Trichostatin A	DM9C8NX	Investigative	Trichostatin A decreases the expression of IST1 homolog (IST1).	[13]
methyl p-hydroxybenzoate	DMO58UW	Investigative	methyl p-hydroxybenzoate increases the expression of IST1 homolog (IST1).	[14]
GALLICACID	DM6Y3A0	Investigative	GALLICACID increases the expression of IST1 homolog (IST1).	[15]

References

• [1] Epigenetic down-regulation of the HIST1 locus predicts better prognosis in acute myeloid leukemia with NPM1 mutation.Clin Epigenetics. 2019 Oct 12;11(1):141. doi: 10.1186/s13148-019-0738-6.
• [2] OLC1 is overexpressed in breast cancer and its expression correlates with poor patient survival.Tumour Biol. 2014 Sep;35(9):8823-7. doi: 10.1007/s13277-014-2130-7. Epub 2014 Jun 1.
• [3] Association analysis identifies 65 new breast cancer risk loci.Nature. 2017 Nov 2;551(7678):92-94. doi: 10.1038/nature24284. Epub 2017 Oct 23.
• [4] Regulation of OLC1 protein expression by the anaphase-promoting complex.Oncol Lett. 2019 Mar;17(3):2639-2646. doi: 10.3892/ol.2019.9881. Epub 2019 Jan 2.
• [5] Overexpression of OLC1 promotes tumorigenesis of human esophageal squamous cell carcinoma.PLoS One. 2014 Mar 7;9(3):e90958. doi: 10.1371/journal.pone.0090958. eCollection 2014.
• [6] Nuclear overexpression of the overexpressed in lung cancer 1 predicts worse prognosis in gastric adenocarcinoma.Oncotarget. 2017 Feb 7;8(6):9442-9450. doi: 10.18632/oncotarget.14217.
• [7] Overexpression of OLC1, cigarette smoke, and human lung tumorigenesis.J Natl Cancer Inst. 2008 Nov 19;100(22):1592-605. doi: 10.1093/jnci/djn379. Epub 2008 Nov 11.
• [8] Human embryonic stem cell-derived test systems for developmental neurotoxicity: a transcriptomics approach. Arch Toxicol. 2013 Jan;87(1):123-43.
• [9] 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.
• [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] 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.
• [12] Low-dose Bisphenol A exposure alters the functionality and cellular environment in a human cardiomyocyte model. Environ Pollut. 2023 Oct 15;335:122359. doi: 10.1016/j.envpol.2023.122359. Epub 2023 Aug 9.
• [13] 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.
• [14] Transcriptome dynamics of alternative splicing events revealed early phase of apoptosis induced by methylparaben in H1299 human lung carcinoma cells. Arch Toxicol. 2020 Jan;94(1):127-140. doi: 10.1007/s00204-019-02629-w. Epub 2019 Nov 20.
• [15] 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.