Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTJGE772)

• DOT Name: Glutathione-specific gamma-glutamylcyclotransferase 1 (CHAC1)
• Synonyms: Gamma-GCG 1; EC 4.3.2.7; Blocks Notch protein; Botch; Cation transport regulator-like protein 1
• Gene Name: CHAC1
• Related Disease:
  Neoplasm
  Advanced cancer
  Burkitt lymphoma
  Cystic fibrosis
  Glioma
  Head-neck squamous cell carcinoma
  Breast cancer
  Breast carcinoma
  Breast neoplasm
  Epithelial ovarian cancer
  Glioblastoma multiforme
  Metastatic malignant neoplasm
  Neuroblastoma
  Ovarian cancer
  Ovarian neoplasm
  Uveal Melanoma
• UniProt ID: CHAC1_HUMAN
• EC Number: 4.3.2.7
• Pfam ID: PF04752
• Sequence:
  MKQESAAPNTPPTSQSPTPSAQFPRNDGDPQALWIFGYGSLVWRPDFAYSDSRVGFVRGY
  SRRFWQGDTFHRGSDKMPGRVVTLLEDHEGCTWGVAYQVQGEQVSKALKYLNVREAVLGG
  YDTKEVTFYPQDAPDQPLKALAYVATPQNPGYLGPAPEEAIATQILACRGFSGHNLEYLL
  RLADFMQLCGPQAQDEHLAAIVDAVGTMLPCFCPTEQALALV
• Function: Catalyzes the cleavage of glutathione into 5-oxo-L-proline and a Cys-Gly dipeptide. Acts specifically on glutathione, but not on other gamma-glutamyl peptides. Glutathione depletion is an important factor for apoptosis initiation and execution. Acts as a pro-apoptotic component of the unfolded protein response pathway by mediating the pro-apoptotic effects of the ATF4-ATF3-DDIT3/CHOP cascade. Negative regulator of Notch signaling pathway involved in embryonic neurogenesis: acts by inhibiting Notch cleavage by furin, maintaining Notch in an immature inactive form, thereby promoting neurogenesis in embryos.
• KEGG Pathway:
  Glutathione metabolism (hsa00480)
  Metabolic pathways (hsa01100)
• Reactome Pathway:
  Response of EIF2AK1 (HRI) to heme deficiency (R-HSA-9648895)
  Glutathione synthesis and recycling (R-HSA-174403)
• BioCyc Pathway: MetaCyc:ENSG00000128965-MONOMER

Molecular Interaction Atlas (MIA) of This DOT

16 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Neoplasm	DISZKGEW	Definitive	Biomarker	[1]
Advanced cancer	DISAT1Z9	Strong	Altered Expression	[2]
Burkitt lymphoma	DIS9D5XU	Strong	Biomarker	[3]
Cystic fibrosis	DIS2OK1Q	Strong	Biomarker	[4]
Glioma	DIS5RPEH	Strong	Biomarker	[5]
Head-neck squamous cell carcinoma	DISF7P24	Strong	Altered Expression	[6]
Breast cancer	DIS7DPX1	Limited	Altered Expression	[7]
Breast carcinoma	DIS2UE88	Limited	Altered Expression	[7]
Breast neoplasm	DISNGJLM	Limited	Altered Expression	[8]
Epithelial ovarian cancer	DIS56MH2	Limited	Altered Expression	[8]
Glioblastoma multiforme	DISK8246	Limited	Altered Expression	[9]
Metastatic malignant neoplasm	DIS86UK6	Limited	Altered Expression	[2]
Neuroblastoma	DISVZBI4	Limited	Altered Expression	[10]
Ovarian cancer	DISZJHAP	Limited	Altered Expression	[8]
Ovarian neoplasm	DISEAFTY	Limited	Altered Expression	[8]
Uveal Melanoma	DISA7ZGL	Limited	Altered Expression	[2]

1 Drug(s) Affected the Post-Translational Modifications of This DOT

Drug Name	Drug ID	Highest Status	Interaction	REF
Valproate	DMCFE9I	Approved	Valproate increases the methylation of Glutathione-specific gamma-glutamylcyclotransferase 1 (CHAC1).	[11]

41 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 Glutathione-specific gamma-glutamylcyclotransferase 1 (CHAC1).	[12]
Acetaminophen	DMUIE76	Approved	Acetaminophen increases the expression of Glutathione-specific gamma-glutamylcyclotransferase 1 (CHAC1).	[13]
Cisplatin	DMRHGI9	Approved	Cisplatin increases the expression of Glutathione-specific gamma-glutamylcyclotransferase 1 (CHAC1).	[14]
Estradiol	DMUNTE3	Approved	Estradiol increases the expression of Glutathione-specific gamma-glutamylcyclotransferase 1 (CHAC1).	[15]
Arsenic trioxide	DM61TA4	Approved	Arsenic trioxide increases the expression of Glutathione-specific gamma-glutamylcyclotransferase 1 (CHAC1).	[16]
Carbamazepine	DMZOLBI	Approved	Carbamazepine affects the expression of Glutathione-specific gamma-glutamylcyclotransferase 1 (CHAC1).	[17]
Marinol	DM70IK5	Approved	Marinol increases the expression of Glutathione-specific gamma-glutamylcyclotransferase 1 (CHAC1).	[18]
Zoledronate	DMIXC7G	Approved	Zoledronate increases the expression of Glutathione-specific gamma-glutamylcyclotransferase 1 (CHAC1).	[19]
Progesterone	DMUY35B	Approved	Progesterone increases the expression of Glutathione-specific gamma-glutamylcyclotransferase 1 (CHAC1).	[20]
Panobinostat	DM58WKG	Approved	Panobinostat increases the expression of Glutathione-specific gamma-glutamylcyclotransferase 1 (CHAC1).	[21]
Dexamethasone	DMMWZET	Approved	Dexamethasone decreases the expression of Glutathione-specific gamma-glutamylcyclotransferase 1 (CHAC1).	[22]
Niclosamide	DMJAGXQ	Approved	Niclosamide increases the expression of Glutathione-specific gamma-glutamylcyclotransferase 1 (CHAC1).	[23]
Cannabidiol	DM0659E	Approved	Cannabidiol increases the expression of Glutathione-specific gamma-glutamylcyclotransferase 1 (CHAC1).	[18]
Bortezomib	DMNO38U	Approved	Bortezomib increases the expression of Glutathione-specific gamma-glutamylcyclotransferase 1 (CHAC1).	[24]
Hydroquinone	DM6AVR4	Approved	Hydroquinone decreases the expression of Glutathione-specific gamma-glutamylcyclotransferase 1 (CHAC1).	[25]
Sodium lauryl sulfate	DMLJ634	Approved	Sodium lauryl sulfate increases the expression of Glutathione-specific gamma-glutamylcyclotransferase 1 (CHAC1).	[26]
Dasatinib	DMJV2EK	Approved	Dasatinib increases the expression of Glutathione-specific gamma-glutamylcyclotransferase 1 (CHAC1).	[27]
Indomethacin	DMSC4A7	Approved	Indomethacin increases the expression of Glutathione-specific gamma-glutamylcyclotransferase 1 (CHAC1).	[28]
Amphotericin B	DMTAJQE	Approved	Amphotericin B increases the expression of Glutathione-specific gamma-glutamylcyclotransferase 1 (CHAC1).	[29]
Cyclophosphamide	DM4O2Z7	Approved	Cyclophosphamide decreases the expression of Glutathione-specific gamma-glutamylcyclotransferase 1 (CHAC1).	[30]
Lindane	DMB8CNL	Approved	Lindane increases the expression of Glutathione-specific gamma-glutamylcyclotransferase 1 (CHAC1).	[16]
Racecadotril	DMFOTZ7	Approved	Racecadotril increases the expression of Glutathione-specific gamma-glutamylcyclotransferase 1 (CHAC1).	[31]
Urethane	DM7NSI0	Phase 4	Urethane increases the expression of Glutathione-specific gamma-glutamylcyclotransferase 1 (CHAC1).	[32]
SNDX-275	DMH7W9X	Phase 3	SNDX-275 decreases the expression of Glutathione-specific gamma-glutamylcyclotransferase 1 (CHAC1).	[33]
Genistein	DM0JETC	Phase 2/3	Genistein increases the expression of Glutathione-specific gamma-glutamylcyclotransferase 1 (CHAC1).	[34]
Amiodarone	DMUTEX3	Phase 2/3 Trial	Amiodarone increases the expression of Glutathione-specific gamma-glutamylcyclotransferase 1 (CHAC1).	[35]
PEITC	DMOMN31	Phase 2	PEITC increases the expression of Glutathione-specific gamma-glutamylcyclotransferase 1 (CHAC1).	[36]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene decreases the expression of Glutathione-specific gamma-glutamylcyclotransferase 1 (CHAC1).	[30]
(+)-JQ1	DM1CZSJ	Phase 1	(+)-JQ1 increases the expression of Glutathione-specific gamma-glutamylcyclotransferase 1 (CHAC1).	[37]
PMID28460551-Compound-2	DM4DOUB	Patented	PMID28460551-Compound-2 increases the expression of Glutathione-specific gamma-glutamylcyclotransferase 1 (CHAC1).	[38]
THAPSIGARGIN	DMDMQIE	Preclinical	THAPSIGARGIN decreases the expression of Glutathione-specific gamma-glutamylcyclotransferase 1 (CHAC1).	[39]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A decreases the expression of Glutathione-specific gamma-glutamylcyclotransferase 1 (CHAC1).	[40]
Trichostatin A	DM9C8NX	Investigative	Trichostatin A affects the expression of Glutathione-specific gamma-glutamylcyclotransferase 1 (CHAC1).	[41]
Formaldehyde	DM7Q6M0	Investigative	Formaldehyde increases the expression of Glutathione-specific gamma-glutamylcyclotransferase 1 (CHAC1).	[42]
Acetaldehyde	DMJFKG4	Investigative	Acetaldehyde increases the expression of Glutathione-specific gamma-glutamylcyclotransferase 1 (CHAC1).	[43]
Deguelin	DMXT7WG	Investigative	Deguelin increases the expression of Glutathione-specific gamma-glutamylcyclotransferase 1 (CHAC1).	[44]
3R14S-OCHRATOXIN A	DM2KEW6	Investigative	3R14S-OCHRATOXIN A decreases the expression of Glutathione-specific gamma-glutamylcyclotransferase 1 (CHAC1).	[30]
Paraquat	DMR8O3X	Investigative	Paraquat increases the expression of Glutathione-specific gamma-glutamylcyclotransferase 1 (CHAC1).	[45]
crotylaldehyde	DMTWRQI	Investigative	crotylaldehyde increases the expression of Glutathione-specific gamma-glutamylcyclotransferase 1 (CHAC1).	[46]
Chlorpyrifos	DMKPUI6	Investigative	Chlorpyrifos increases the expression of Glutathione-specific gamma-glutamylcyclotransferase 1 (CHAC1).	[31]
Bilirubin	DMI0V4O	Investigative	Bilirubin increases the expression of Glutathione-specific gamma-glutamylcyclotransferase 1 (CHAC1).	[47]

References

• [1] Helicobacter pylori induces somatic mutations in TP53 via overexpression of CHAC1 in infected gastric epithelial cells.FEBS Open Bio. 2018 Mar 9;8(4):671-679. doi: 10.1002/2211-5463.12402. eCollection 2018 Apr.
• [2] Higher expression of cation transport regulator-like protein 1 (CHAC1) predicts of poor outcomes in uveal melanoma (UM) patients.Int Ophthalmol. 2019 Dec;39(12):2825-2832. doi: 10.1007/s10792-019-01129-1. Epub 2019 Jun 3.
• [3] Artesunate activates the ATF4-CHOP-CHAC1 pathway and affects ferroptosis in Burkitt's Lymphoma.Biochem Biophys Res Commun. 2019 Nov 12;519(3):533-539. doi: 10.1016/j.bbrc.2019.09.023. Epub 2019 Sep 16.
• [4] CHAC1 Is Differentially Expressed in Normal and Cystic Fibrosis Bronchial Epithelial Cells and Regulates the Inflammatory Response Induced by Pseudomonas aeruginosa.Front Immunol. 2018 Nov 29;9:2823. doi: 10.3389/fimmu.2018.02823. eCollection 2018.
• [5] The CHAC1-inhibited Notch3 pathway is involved in temozolomide-induced glioma cytotoxicity.Neuropharmacology. 2017 Apr;116:300-314. doi: 10.1016/j.neuropharm.2016.12.011. Epub 2016 Dec 13.
• [6] Nisin, an apoptogenic bacteriocin and food preservative, attenuates HNSCC tumorigenesis via CHAC1.Cancer Med. 2012 Dec;1(3):295-305. doi: 10.1002/cam4.35. Epub 2012 Oct 2.
• [7] Development of a novel prognostic score for breast cancer patients using mRNA expression of CHAC1.J Comp Eff Res. 2017 Oct;6(7):563-574. doi: 10.2217/cer-2017-0015. Epub 2017 Sep 19.
• [8] Elevated mRNA expression of CHAC1 splicing variants is associated with poor outcome for breast and ovarian cancer patients.Br J Cancer. 2012 Jan 3;106(1):189-98. doi: 10.1038/bjc.2011.510. Epub 2011 Nov 22.
• [9] Characterization of a FOXG1:TLE1 transcriptional network in glioblastoma-initiating cells.Mol Oncol. 2018 Jun;12(6):775-787. doi: 10.1002/1878-0261.12168. Epub 2018 Apr 27.
• [10] Upregulation of LYAR induces neuroblastoma cell proliferation and survival.Cell Death Differ. 2017 Sep;24(9):1645-1654. doi: 10.1038/cdd.2017.98. Epub 2017 Jul 7.
• [11] 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.
• [12] Inter-laboratory comparison of human renal proximal tubule (HK-2) transcriptome alterations due to Cyclosporine A exposure and medium exhaustion. Toxicol In Vitro. 2009 Apr;23(3):486-99.
• [13] Gene expression analysis of precision-cut human liver slices indicates stable expression of ADME-Tox related genes. Toxicol Appl Pharmacol. 2011 May 15;253(1):57-69.
• [14] The thioxotriazole copper(II) complex A0 induces endoplasmic reticulum stress and paraptotic death in human cancer cells. J Biol Chem. 2009 Sep 4;284(36):24306-19.
• [15] 17-Estradiol Activates HSF1 via MAPK Signaling in ER-Positive Breast Cancer Cells. Cancers (Basel). 2019 Oct 11;11(10):1533. doi: 10.3390/cancers11101533.
• [16] Toxicogenomics-based identification of mechanisms for direct immunotoxicity. Toxicol Sci. 2013 Oct;135(2):328-46.
• [17] Gene Expression Regulation and Pathway Analysis After Valproic Acid and Carbamazepine Exposure in a Human Embryonic Stem Cell-Based Neurodevelopmental Toxicity Assay. Toxicol Sci. 2015 Aug;146(2):311-20. doi: 10.1093/toxsci/kfv094. Epub 2015 May 15.
• [18] Inhibiting Heat Shock Proteins Can Potentiate the Cytotoxic Effect of Cannabidiol in Human Glioma Cells. Anticancer Res. 2015 Nov;35(11):5827-37.
• [19] The proapoptotic effect of zoledronic acid is independent of either the bone microenvironment or the intrinsic resistance to bortezomib of myeloma cells and is enhanced by the combination with arsenic trioxide. Exp Hematol. 2011 Jan;39(1):55-65.
• [20] Gene expression in endometrial cancer cells (Ishikawa) after short time high dose exposure to progesterone. Steroids. 2008 Jan;73(1):116-28.
• [21] 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.
• [22] Identification of mechanisms of action of bisphenol a-induced human preadipocyte differentiation by transcriptional profiling. Obesity (Silver Spring). 2014 Nov;22(11):2333-43.
• [23] Mitochondrial Uncoupling Induces Epigenome Remodeling and Promotes Differentiation in Neuroblastoma. Cancer Res. 2023 Jan 18;83(2):181-194. doi: 10.1158/0008-5472.CAN-22-1029.
• [24] Proteasome inhibitor PS-341 induces apoptosis through induction of endoplasmic reticulum stress-reactive oxygen species in head and neck squamous cell carcinoma cells. Mol Cell Biol. 2004 Nov;24(22):9695-704. doi: 10.1128/MCB.24.22.9695-9704.2004.
• [25] Differently expressed long noncoding RNAs and mRNAs in TK6 cells exposed to low dose hydroquinone. Oncotarget. 2017 Oct 4;8(56):95554-95567. doi: 10.18632/oncotarget.21481. eCollection 2017 Nov 10.
• [26] CXCL14 downregulation in human keratinocytes is a potential biomarker for a novel in vitro skin sensitization test. Toxicol Appl Pharmacol. 2020 Jan 1;386:114828. doi: 10.1016/j.taap.2019.114828. Epub 2019 Nov 14.
• [27] Dasatinib reverses cancer-associated fibroblasts (CAFs) from primary lung carcinomas to a phenotype comparable to that of normal fibroblasts. Mol Cancer. 2010 Jun 27;9:168.
• [28] Anti-inflammatory agent indomethacin reduces invasion and alters metabolism in a human breast cancer cell line. Neoplasia. 2007 Mar;9(3):222-35.
• [29] Differential expression of microRNAs and their predicted targets in renal cells exposed to amphotericin B and its complex with copper (II) ions. Toxicol Mech Methods. 2017 Sep;27(7):537-543. doi: 10.1080/15376516.2017.1333554. Epub 2017 Jun 8.
• [30] Transcriptome-based functional classifiers for direct immunotoxicity. Arch Toxicol. 2014 Mar;88(3):673-89.
• [31] Successful validation of genomic biomarkers for human immunotoxicity in Jurkat T cells in vitro. J Appl Toxicol. 2015 Jul;35(7):831-41.
• [32] Ethyl carbamate induces cell death through its effects on multiple metabolic pathways. Chem Biol Interact. 2017 Nov 1;277:21-32.
• [33] 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.
• [34] Dose- and time-dependent transcriptional response of Ishikawa cells exposed to genistein. Toxicol Sci. 2016 May;151(1):71-87.
• [35] Identification by automated screening of a small molecule that selectively eliminates neural stem cells derived from hESCs but not dopamine neurons. PLoS One. 2009 Sep 23;4(9):e7155.
• [36] Phenethyl isothiocyanate alters the gene expression and the levels of protein associated with cell cycle regulation in human glioblastoma GBM 8401 cells. Environ Toxicol. 2017 Jan;32(1):176-187.
• [37] CCAT1 is an enhancer-templated RNA that predicts BET sensitivity in colorectal cancer. J Clin Invest. 2016 Feb;126(2):639-52.
• [38] Cell-based two-dimensional morphological assessment system to predict cancer drug-induced cardiotoxicity using human induced pluripotent stem cell-derived cardiomyocytes. Toxicol Appl Pharmacol. 2019 Nov 15;383:114761. doi: 10.1016/j.taap.2019.114761. Epub 2019 Sep 15.
• [39] The genome-wide expression profile of Scrophularia ningpoensis-treated thapsigargin-stimulated U-87MG cells. Neurotoxicology. 2009 May;30(3):368-76.
• [40] Epigenetic influences of low-dose bisphenol A in primary human breast epithelial cells. Toxicol Appl Pharmacol. 2010 Oct 15;248(2):111-21.
• [41] A trichostatin A expression signature identified by TempO-Seq targeted whole transcriptome profiling. PLoS One. 2017 May 25;12(5):e0178302. doi: 10.1371/journal.pone.0178302. eCollection 2017.
• [42] Identification of gene markers for formaldehyde exposure in humans. Environ Health Perspect. 2007 Oct;115(10):1460-6. doi: 10.1289/ehp.10180.
• [43] Transcriptome profile analysis of saturated aliphatic aldehydes reveals carbon number-specific molecules involved in pulmonary toxicity. Chem Res Toxicol. 2014 Aug 18;27(8):1362-70.
• [44] Neurotoxicity and underlying cellular changes of 21 mitochondrial respiratory chain inhibitors. Arch Toxicol. 2021 Feb;95(2):591-615. doi: 10.1007/s00204-020-02970-5. Epub 2021 Jan 29.
• [45] An in vitro strategy using multiple human induced pluripotent stem cell-derived models to assess the toxicity of chemicals: A case study on paraquat. Toxicol In Vitro. 2022 Jun;81:105333. doi: 10.1016/j.tiv.2022.105333. Epub 2022 Feb 16.
• [46] Gene expression profile and cytotoxicity of human bronchial epithelial cells exposed to crotonaldehyde. Toxicol Lett. 2010 Aug 16;197(2):113-22.
• [47] Global changes in gene regulation demonstrate that unconjugated bilirubin is able to upregulate and activate select components of the endoplasmic reticulum stress response pathway. J Biochem Mol Toxicol. 2010 Mar-Apr;24(2):73-88.