Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTVS7S2H)

• DOT Name: CDGSH iron-sulfur domain-containing protein 2 (CISD2)
• Synonyms: Endoplasmic reticulum intermembrane small protein; MitoNEET-related 1 protein; Miner1; Nutrient-deprivation autophagy factor-1; NAF-1
• Gene Name: CISD2
• Related Disease:
  Waardenburg syndrome type 1
  Wolfram syndrome
  Wolfram syndrome 1
  Alzheimer disease
  Breast cancer
  Breast carcinoma
  Coagulation defect
  Diabetes insipidus
  Glioma
  Head and neck cancer
  Head and neck carcinoma
  Hepatocellular carcinoma
  High blood pressure
  Mental disorder
  Neoplasm
  Non-alcoholic fatty liver disease
  Non-alcoholic steatohepatitis
  Obesity
  Waardenburg syndrome type 2A
  Wolfram syndrome 2
  Advanced cancer
  Autoimmune disease
  Dementia
  Gastric cancer
  Stomach cancer
  Type-1/2 diabetes
  Carcinoma of liver and intrahepatic biliary tract
  Liver cancer
  Lung adenocarcinoma
  Lung cancer
  Lung carcinoma
  Neuroblastoma
  Non-insulin dependent diabetes
  Pancreatic cancer
• UniProt ID: CISD2_HUMAN
• PDB ID: 3FNV; 4OO7; 4OOA; 7P0P
• Pfam ID: PF10660 ; PF09360
• Sequence:
  MVLESVARIVKVQLPAYLKRLPVPESITGFARLTVSEWLRLLPFLGVLALLGYLAVRPFL
  PKKKQQKDSLINLKIQKENPKVVNEINIEDLCLTKAAYCRCWRSKTFPACDGSHNKHNEL
  TGDNVGPLILKKKEV
• Function: Regulator of autophagy that contributes to antagonize BECN1-mediated cellular autophagy at the endoplasmic reticulum. Participates in the interaction of BCL2 with BECN1 and is required for BCL2-mediated depression of endoplasmic reticulum Ca(2+) stores during autophagy. Contributes to BIK-initiated autophagy, while it is not involved in BIK-dependent activation of caspases. Involved in life span control, probably via its function as regulator of autophagy.
• Tissue Specificity: Testis, small intestine, kidney, lung, brain, heart, pancreas and platelets.

Molecular Interaction Atlas (MIA) of This DOT

34 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Waardenburg syndrome type 1	DIS8DBQ5	Definitive	Biomarker	[1]
Wolfram syndrome	DISN16XW	Definitive	Autosomal recessive	[2]
Wolfram syndrome 1	DISC2P61	Definitive	Biomarker	[1]
Alzheimer disease	DISF8S70	Strong	Biomarker	[3]
Breast cancer	DIS7DPX1	Strong	Biomarker	[4]
Breast carcinoma	DIS2UE88	Strong	Biomarker	[4]
Coagulation defect	DIS9X3H6	Strong	Biomarker	[5]
Diabetes insipidus	DIS0U6CJ	Strong	Genetic Variation	[6]
Glioma	DIS5RPEH	Strong	Altered Expression	[7]
Head and neck cancer	DISBPSQZ	Strong	Biomarker	[8]
Head and neck carcinoma	DISOU1DS	Strong	Biomarker	[8]
Hepatocellular carcinoma	DIS0J828	Strong	Altered Expression	[9]
High blood pressure	DISY2OHH	Strong	Genetic Variation	[10]
Mental disorder	DIS3J5R8	Strong	Genetic Variation	[6]
Neoplasm	DISZKGEW	Strong	Altered Expression	[11]
Non-alcoholic fatty liver disease	DISDG1NL	Strong	Biomarker	[12]
Non-alcoholic steatohepatitis	DIST4788	Strong	Biomarker	[12]
Obesity	DIS47Y1K	Strong	Biomarker	[13]
Waardenburg syndrome type 2A	DISM4IVI	Strong	Genetic Variation	[6]
Wolfram syndrome 2	DISEO4HZ	Strong	Autosomal recessive	[14]
Advanced cancer	DISAT1Z9	moderate	Biomarker	[15]
Autoimmune disease	DISORMTM	moderate	Biomarker	[16]
Dementia	DISXL1WY	moderate	Genetic Variation	[10]
Gastric cancer	DISXGOUK	moderate	Altered Expression	[17]
Stomach cancer	DISKIJSX	moderate	Altered Expression	[17]
Type-1/2 diabetes	DISIUHAP	moderate	Biomarker	[18]
Carcinoma of liver and intrahepatic biliary tract	DIS8WA0W	Limited	Altered Expression	[19]
Liver cancer	DISDE4BI	Limited	Altered Expression	[19]
Lung adenocarcinoma	DISD51WR	Limited	Altered Expression	[20]
Lung cancer	DISCM4YA	Limited	Biomarker	[20]
Lung carcinoma	DISTR26C	Limited	Biomarker	[20]
Neuroblastoma	DISVZBI4	Limited	Biomarker	[21]
Non-insulin dependent diabetes	DISK1O5Z	Limited	Biomarker	[22]
Pancreatic cancer	DISJC981	Limited	Biomarker	[23]

6 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 CDGSH iron-sulfur domain-containing protein 2 (CISD2).	[24]
Tretinoin	DM49DUI	Approved	Tretinoin decreases the expression of CDGSH iron-sulfur domain-containing protein 2 (CISD2).	[25]
Doxorubicin	DMVP5YE	Approved	Doxorubicin decreases the expression of CDGSH iron-sulfur domain-containing protein 2 (CISD2).	[26]
Ivermectin	DMDBX5F	Approved	Ivermectin decreases the expression of CDGSH iron-sulfur domain-containing protein 2 (CISD2).	[27]
Vorinostat	DMWMPD4	Approved	Vorinostat increases the expression of CDGSH iron-sulfur domain-containing protein 2 (CISD2).	[28]
Milchsaure	DM462BT	Investigative	Milchsaure decreases the expression of CDGSH iron-sulfur domain-containing protein 2 (CISD2).	[29]

References

• [1] Wolfram syndrome 1 and Wolfram syndrome 2.Curr Opin Pediatr. 2012 Aug;24(4):512-7. doi: 10.1097/MOP.0b013e328354ccdf.
• [2] Technical standards for the interpretation and reporting of constitutional copy-number variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics (ACMG) and the Clinical Genome Resource (ClinGen). Genet Med. 2020 Feb;22(2):245-257. doi: 10.1038/s41436-019-0686-8. Epub 2019 Nov 6.
• [3] Upregulation of Cisd2 attenuates Alzheimer's-related neuronal loss in mice.J Pathol. 2020 Mar;250(3):299-311. doi: 10.1002/path.5374. Epub 2020 Jan 13.
• [4] The anti-apoptotic proteins NAF-1 and iASPP interact to drive apoptosis in cancer cells.Chem Sci. 2018 Nov 20;10(3):665-673. doi: 10.1039/c8sc03390k. eCollection 2019 Jan 21.
• [5] A novel CISD2 mutation associated with a classical Wolfram syndrome phenotype alters Ca2+ homeostasis and ER-mitochondria interactions. Hum Mol Genet. 2017 May 1;26(9):1599-1611. doi: 10.1093/hmg/ddx060.
• [6] Correction: Genetic and clinical aspects of Wolfram syndrome 1, a severe neurodegenerative disease.Pediatr Res. 2018 Nov;84(5):787. doi: 10.1038/s41390-018-0146-1.
• [7] CISD2 promotes the proliferation of glioma cells via suppressing beclin?mediated autophagy and is targeted by microRNA?49a.Mol Med Rep. 2017 Dec;16(6):7939-7948. doi: 10.3892/mmr.2017.7642. Epub 2017 Sep 27.
• [8] CISD2 inhibition overcomes resistance to sulfasalazine-induced ferroptotic cell death in head and neck cancer.Cancer Lett. 2018 Sep 28;432:180-190. doi: 10.1016/j.canlet.2018.06.018. Epub 2018 Jun 18.
• [9] Binding of thiazolidinediones to the endoplasmic reticulum protein nutrient-deprivation autophagy factor-1.Bioorg Med Chem Lett. 2019 Apr 1;29(7):901-904. doi: 10.1016/j.bmcl.2019.01.041. Epub 2019 Feb 1.
• [10] Sequence variants of the aging gene CISD2 and the risk for Alzheimer's disease.J Formos Med Assoc. 2015 Jul;114(7):627-32. doi: 10.1016/j.jfma.2013.02.012. Epub 2013 Apr 8.
• [11] CDGSH Iron Sulfur Domain 2 Activates Proliferation and EMT of Pancreatic Cancer Cells via Wnt/-Catenin Pathway and Has Prognostic Value in Human Pancreatic Cancer.Oncol Res. 2017 Apr 14;25(4):605-615. doi: 10.3727/096504016X14767450526417. Epub 2016 Oct 26.
• [12] CISD2 Haploinsufficiency Disrupts Calcium Homeostasis, Causes Nonalcoholic Fatty Liver Disease, and Promotes Hepatocellular Carcinoma.Cell Rep. 2017 Nov 21;21(8):2198-2211. doi: 10.1016/j.celrep.2017.10.099.
• [13] Structure-function analysis of NEET proteins uncovers their role as key regulators of iron and ROS homeostasis in health and disease.Biochim Biophys Acta. 2015 Jun;1853(6):1294-315. doi: 10.1016/j.bbamcr.2014.10.014. Epub 2014 Oct 23.
• [14] The Gene Curation Coalition: A global effort to harmonize gene-disease evidence resources. Genet Med. 2022 Aug;24(8):1732-1742. doi: 10.1016/j.gim.2022.04.017. Epub 2022 May 4.
• [15] Structure of the human monomeric NEET protein MiNT and its role in regulating iron and reactive oxygen species in cancer cells.Proc Natl Acad Sci U S A. 2018 Jan 9;115(2):272-277. doi: 10.1073/pnas.1715842115. Epub 2017 Dec 19.
• [16] USP49 negatively regulates cellular antiviral responses via deconjugating K63-linked ubiquitination of MITA.PLoS Pathog. 2019 Apr 3;15(4):e1007680. doi: 10.1371/journal.ppat.1007680. eCollection 2019 Apr.
• [17] CISD2 enhances the chemosensitivity of gastric cancer through the enhancement of 5-FU-induced apoptosis and the inhibition of autophagy by AKT/mTOR pathway.Cancer Med. 2017 Oct;6(10):2331-2346. doi: 10.1002/cam4.1169. Epub 2017 Aug 31.
• [18] Interactions between mitoNEET and NAF-1 in cells.PLoS One. 2017 Apr 20;12(4):e0175796. doi: 10.1371/journal.pone.0175796. eCollection 2017.
• [19] CISD2 associated with proliferation indicates negative prognosis in patients with hepatocellular carcinoma.Int J Clin Exp Pathol. 2015 Oct 1;8(10):13725-38. eCollection 2015.
• [20] Upregulation of CISD2 augments ROS homeostasis and contributes to tumorigenesis and poor prognosis of lung adenocarcinoma.Sci Rep. 2017 Sep 19;7(1):11893. doi: 10.1038/s41598-017-12131-x.
• [21] CDGSH Iron Sulfur Domain 2 Deficiency Inhibits Cell Proliferation and Induces Cell Differentiation of Neuroblastoma.Pathol Oncol Res. 2020 Jul;26(3):1725-1733. doi: 10.1007/s12253-019-00753-7. Epub 2019 Oct 22.
• [22] Binding of Nitric Oxide in CDGSH-type [2Fe-2S] Clusters of the Human Mitochondrial Protein Miner2.J Biol Chem. 2017 Feb 24;292(8):3146-3153. doi: 10.1074/jbc.M116.766774. Epub 2017 Jan 12.
• [23] Resveratrol-Induced Downregulation of NAF-1 Enhances the Sensitivity of Pancreatic Cancer Cells to Gemcitabine via the ROS/Nrf2 Signaling Pathways.Oxid Med Cell Longev. 2018 Mar 22;2018:9482018. doi: 10.1155/2018/9482018. eCollection 2018.
• [24] 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.
• [25] 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.
• [26] 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.
• [27] 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.
• [28] 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.
• [29] Transcriptional profiling of lactic acid treated reconstructed human epidermis reveals pathways underlying stinging and itch. Toxicol In Vitro. 2019 Jun;57:164-173.