Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTRX2OSF)

• DOT Name: Helicase-like transcription factor (HLTF)
• Synonyms: EC 2.3.2.27; EC 3.6.4.-; DNA-binding protein/plasminogen activator inhibitor 1 regulator; HIP116; RING finger protein 80; RING-type E3 ubiquitin transferase HLTF; SWI/SNF-related matrix-associated actin-dependent regulator of chromatin subfamily A member 3; Sucrose nonfermenting protein 2-like 3
• Gene Name: HLTF
• Related Disease:
  Acute myelogenous leukaemia
  Cervical cancer
  Cervical carcinoma
  Colorectal carcinoma
  Esophageal cancer
  Kidney neoplasm
  Adenocarcinoma
  Adenoma
  Advanced cancer
  Carcinoma
  Chromosomal disorder
  Colon cancer
  Colon carcinoma
  Colonic neoplasm
  Esophageal squamous cell carcinoma
  Familial adenomatous polyposis
  Gastric cancer
  Head and neck cancer
  Head and neck carcinoma
  Hepatocellular carcinoma
  Intestinal cancer
  Kidney cancer
  Lung cancer
  Lung carcinoma
  Lung squamous cell carcinoma
  Metastatic malignant neoplasm
  Myelodysplastic syndrome
  Neoplasm
  Non-small-cell lung cancer
  Ovarian neoplasm
  Squamous cell carcinoma
  Stomach cancer
  High blood pressure
  Thyroid cancer
  Thyroid gland carcinoma
  Thyroid tumor
  46,XY sex reversal 2
  Charcot-Marie-Tooth disease type 3
  Colorectal neoplasm
  Gallbladder cancer
  Gallbladder carcinoma
  Gastric neoplasm
  Polyposis
• UniProt ID: HLTF_HUMAN
• PDB ID: 2MZN; 4HRE; 4HRH; 4S0N; 4XZF; 4XZG; 5BNH; 5K5F; 6KCS
• EC Number: 2.3.2.27; 3.6.4.-
• Pfam ID: PF00271 ; PF08797 ; PF00176 ; PF13923
• Sequence:
  MSWMFKRDPVWKYLQTVQYGVHGNFPRLSYPTFFPRFEFQDVIPPDDFLTSDEEVDSVLF
  GSLRGHVVGLRYYTGVVNNNEMVALQRDPNNPYDKNAIKVNNVNGNQVGHLKKELAGALA
  YIMDNKLAQIEGVVPFGANNAFTMPLHMTFWGKEENRKAVSDQLKKHGFKLGPAPKTLGF
  NLESGWGSGRAGPSYSMPVHAAVQMTTEQLKTEFDKLFEDLKEDDKTHEMEPAEAIETPL
  LPHQKQALAWMVSRENSKELPPFWEQRNDLYYNTITNFSEKDRPENVHGGILADDMGLGK
  TLTAIAVILTNFHDGRPLPIERVKKNLLKKEYNVNDDSMKLGGNNTSEKADGLSKDASRC
  SEQPSISDIKEKSKFRMSELSSSRPKRRKTAVQYIESSDSEEIETSELPQKMKGKLKNVQ
  SETKGRAKAGSSKVIEDVAFACALTSSVPTTKKKMLKKGACAVEGSKKTDVEERPRTTLI
  ICPLSVLSNWIDQFGQHIKSDVHLNFYVYYGPDRIREPALLSKQDIVLTTYNILTHDYGT
  KGDSPLHSIRWLRVILDEGHAIRNPNAQQTKAVLDLESERRWVLTGTPIQNSLKDLWSLL
  SFLKLKPFIDREWWHRTIQRPVTMGDEGGLRRLQSLIKNITLRRTKTSKIKGKPVLELPE
  RKVFIQHITLSDEERKIYQSVKNEGRATIGRYFNEGTVLAHYADVLGLLLRLRQICCHTY
  LLTNAVSSNGPSGNDTPEELRKKLIRKMKLILSSGSDEECAICLDSLTVPVITHCAHVFC
  KPCICQVIQNEQPHAKCPLCRNDIHEDNLLECPPEELARDSEKKSDMEWTSSSKINALMH
  ALTDLRKKNPNIKSLVVSQFTTFLSLIEIPLKASGFVFTRLDGSMAQKKRVESIQCFQNT
  EAGSPTIMLLSLKAGGVGLNLSAASRVFLMDPAWNPAAEDQCFDRCHRLGQKQEVIITKF
  IVKDSVEENMLKIQNKKRELAAGAFGTKKPNADEMKQAKINEIRTLIDL
• Function: Has both helicase and E3 ubiquitin ligase activities. Possesses intrinsic ATP-dependent nucleosome-remodeling activity; This activity may be required for transcriptional activation or repression of specific target promoters. These may include the SERPINE1 and HIV-1 promoters and the SV40 enhancer, to which this protein can bind directly. Plays a role in error-free postreplication repair (PRR) of damaged DNA and maintains genomic stability through acting as a ubiquitin ligase for 'Lys-63'-linked polyubiquitination of chromatin-bound PCNA.
• Tissue Specificity: Expressed in brain, heart, kidney, liver, lung, pancreas, placenta and skeletal muscle.
• Reactome Pathway: E3 ubiquitin ligases ubiquitinate target proteins (R-HSA-8866654)

Molecular Interaction Atlas (MIA) of This DOT

43 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Acute myelogenous leukaemia	DISCSPTN	Definitive	Genetic Variation	[1]
Cervical cancer	DISFSHPF	Definitive	Biomarker	[2]
Cervical carcinoma	DIST4S00	Definitive	Biomarker	[2]
Colorectal carcinoma	DIS5PYL0	Definitive	Genetic Variation	[3]
Esophageal cancer	DISGB2VN	Definitive	Posttranslational Modification	[4]
Kidney neoplasm	DISBNZTN	Definitive	Biomarker	[5]
Adenocarcinoma	DIS3IHTY	Strong	Genetic Variation	[6]
Adenoma	DIS78ZEV	Strong	Biomarker	[7]
Advanced cancer	DISAT1Z9	Strong	Altered Expression	[8]
Carcinoma	DISH9F1N	Strong	Biomarker	[7]
Chromosomal disorder	DISM5BB5	Strong	Altered Expression	[9]
Colon cancer	DISVC52G	Strong	Posttranslational Modification	[7]
Colon carcinoma	DISJYKUO	Strong	Genetic Variation	[10]
Colonic neoplasm	DISSZ04P	Strong	Posttranslational Modification	[7]
Esophageal squamous cell carcinoma	DIS5N2GV	Strong	Posttranslational Modification	[11]
Familial adenomatous polyposis	DISW53RE	Strong	Biomarker	[12]
Gastric cancer	DISXGOUK	Strong	Posttranslational Modification	[13]
Head and neck cancer	DISBPSQZ	Strong	Genetic Variation	[14]
Head and neck carcinoma	DISOU1DS	Strong	Genetic Variation	[14]
Hepatocellular carcinoma	DIS0J828	Strong	Genetic Variation	[15]
Intestinal cancer	DISYCNF1	Strong	Biomarker	[7]
Kidney cancer	DISBIPKM	Strong	Biomarker	[16]
Lung cancer	DISCM4YA	Strong	Altered Expression	[6]
Lung carcinoma	DISTR26C	Strong	Altered Expression	[6]
Lung squamous cell carcinoma	DISXPIBD	Strong	Genetic Variation	[6]
Metastatic malignant neoplasm	DIS86UK6	Strong	Altered Expression	[8]
Myelodysplastic syndrome	DISYHNUI	Strong	Genetic Variation	[1]
Neoplasm	DISZKGEW	Strong	Genetic Variation	[3]
Non-small-cell lung cancer	DIS5Y6R9	Strong	Altered Expression	[6]
Ovarian neoplasm	DISEAFTY	Strong	Altered Expression	[16]
Squamous cell carcinoma	DISQVIFL	Strong	Altered Expression	[17]
Stomach cancer	DISKIJSX	Strong	Posttranslational Modification	[13]
High blood pressure	DISY2OHH	moderate	Altered Expression	[18]
Thyroid cancer	DIS3VLDH	moderate	Biomarker	[19]
Thyroid gland carcinoma	DISMNGZ0	moderate	Altered Expression	[19]
Thyroid tumor	DISLVKMD	moderate	Biomarker	[19]
46,XY sex reversal 2	DIS0USUN	Limited	Genetic Variation	[3]
Charcot-Marie-Tooth disease type 3	DIS6DQK1	Limited	Genetic Variation	[3]
Colorectal neoplasm	DISR1UCN	Limited	Genetic Variation	[3]
Gallbladder cancer	DISXJUAF	Limited	Biomarker	[20]
Gallbladder carcinoma	DISD6ACL	Limited	Biomarker	[20]
Gastric neoplasm	DISOKN4Y	Limited	Posttranslational Modification	[16]
Polyposis	DISZSPOK	Limited	Posttranslational Modification	[21]

12 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 Helicase-like transcription factor (HLTF).	[22]
Ciclosporin	DMAZJFX	Approved	Ciclosporin decreases the expression of Helicase-like transcription factor (HLTF).	[23]
Tretinoin	DM49DUI	Approved	Tretinoin decreases the expression of Helicase-like transcription factor (HLTF).	[24]
Acetaminophen	DMUIE76	Approved	Acetaminophen decreases the expression of Helicase-like transcription factor (HLTF).	[25]
Ivermectin	DMDBX5F	Approved	Ivermectin decreases the expression of Helicase-like transcription factor (HLTF).	[26]
Quercetin	DM3NC4M	Approved	Quercetin decreases the expression of Helicase-like transcription factor (HLTF).	[27]
Testosterone	DM7HUNW	Approved	Testosterone decreases the expression of Helicase-like transcription factor (HLTF).	[28]
Nicotine	DMWX5CO	Approved	Nicotine decreases the expression of Helicase-like transcription factor (HLTF).	[30]
Acetic Acid, Glacial	DM4SJ5Y	Approved	Acetic Acid, Glacial decreases the expression of Helicase-like transcription factor (HLTF).	[31]
Motexafin gadolinium	DMEJKRF	Approved	Motexafin gadolinium decreases the expression of Helicase-like transcription factor (HLTF).	[31]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene decreases the expression of Helicase-like transcription factor (HLTF).	[30]
OXYBENZONE	DMMZYX6	Investigative	OXYBENZONE increases the expression of Helicase-like transcription factor (HLTF).	[34]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Decitabine	DMQL8XJ	Approved	Decitabine affects the methylation of Helicase-like transcription factor (HLTF).	[29]
TAK-243	DM4GKV2	Phase 1	TAK-243 increases the sumoylation of Helicase-like transcription factor (HLTF).	[32]
PMID28870136-Compound-52	DMFDERP	Patented	PMID28870136-Compound-52 increases the phosphorylation of Helicase-like transcription factor (HLTF).	[33]

References

• [1] A germline HLTF mutation in familial MDS induces DNA damage accumulation through impaired PCNA polyubiquitination.Leukemia. 2019 Jul;33(7):1773-1782. doi: 10.1038/s41375-019-0385-0. Epub 2019 Jan 29.
• [2] Helicase-like transcription factor confers radiation resistance in cervical cancer through enhancing the DNA damage repair capacity.J Cancer Res Clin Oncol. 2011 Apr;137(4):629-37. doi: 10.1007/s00432-010-0925-5. Epub 2010 Jun 10.
• [3] Helicase-like transcription factor (Hltf) gene-deletion promotes oxidative phosphorylation (OXPHOS) in colorectal tumors of AOM/DSS-treated mice.PLoS One. 2019 Aug 28;14(8):e0221751. doi: 10.1371/journal.pone.0221751. eCollection 2019.
• [4] Methylation pattern of HLTF gene in digestive tract cancers.Int J Cancer. 2003 Apr 20;104(4):433-6. doi: 10.1002/ijc.10985.
• [5] The helicase-like transcription factor and its implication in cancer progression.Cell Mol Life Sci. 2008 Feb;65(4):591-604. doi: 10.1007/s00018-007-7392-4.
• [6] Helicase-like transcription factor expression is associated with a poor prognosis in Non-Small-Cell Lung Cancer (NSCLC).BMC Cancer. 2018 Apr 16;18(1):429. doi: 10.1186/s12885-018-4215-y.
• [7] Loss of HLTF function promotes intestinal carcinogenesis.Mol Cancer. 2012 Mar 27;11:18. doi: 10.1186/1476-4598-11-18.
• [8] DCUN1D1 facilitates tumor metastasis by activating FAK signaling and up-regulates PD-L1 in non-small-cell lung cancer.Exp Cell Res. 2019 Jan 15;374(2):304-314. doi: 10.1016/j.yexcr.2018.12.001. Epub 2018 Dec 4.
• [9] Helicase-like transcription factor is a RUNX1 target whose downregulation promotes genomic instability and correlates with complex cytogenetic features in acute myeloid leukemia.Haematologica. 2016 Apr;101(4):448-57. doi: 10.3324/haematol.2015.137125. Epub 2016 Jan 22.
• [10] DNA hypermethylation and histone hypoacetylation of the HLTF gene are associated with reduced expression in gastric carcinoma.Cancer Sci. 2003 Aug;94(8):692-8. doi: 10.1111/j.1349-7006.2003.tb01504.x.
• [11] Aberrant methylation is frequently observed in advanced esophageal squamous cell carcinoma.Anticancer Res. 2006 Sep-Oct;26(5A):3333-5.
• [12] Quantitative detection of promoter hypermethylation in multiple genes in the serum of patients with colorectal cancer.Am J Gastroenterol. 2005 Oct;100(10):2274-9. doi: 10.1111/j.1572-0241.2005.50412.x.
• [13] Promoter methylation of helicase-like transcription factor is associated with the early stages of gastric cancer with family history.Ann Oncol. 2006 Apr;17(4):657-62. doi: 10.1093/annonc/mdl018. Epub 2006 Feb 23.
• [14] Assessment of DNA repair susceptibility genes identified by whole exome sequencing in head and neck cancer.DNA Repair (Amst). 2018 Jun-Jul;66-67:50-63. doi: 10.1016/j.dnarep.2018.04.005. Epub 2018 Apr 26.
• [15] Loss of heterozygosity and methylation of multiple tumor suppressor genes on chromosome 3 in hepatocellular carcinoma.J Gastroenterol. 2013 Jan;48(1):132-43. doi: 10.1007/s00535-012-0621-0. Epub 2012 Jul 6.
• [16] Early expression of the Helicase-Like Transcription Factor (HLTF/SMARCA3) in an experimental model of estrogen-induced renal carcinogenesis.Mol Cancer. 2006 Jun 8;5:23. doi: 10.1186/1476-4598-5-23.
• [17] Helicase-like transcription factor exhibits increased expression and altered intracellular distribution during tumor progression in hypopharyngeal and laryngeal squamous cell carcinomas.Virchows Arch. 2008 Nov;453(5):491-9. doi: 10.1007/s00428-008-0675-9. Epub 2008 Sep 30.
• [18] Differential expression profile of long non-coding RNAs in human thoracic aortic aneurysm.J Cell Biochem. 2018 Nov;119(10):7991-7997. doi: 10.1002/jcb.26670. Epub 2018 Jun 28.
• [19] Helicase-like transcription factor: a new marker of well-differentiated thyroid cancers.BMC Cancer. 2014 Jul 8;14:492. doi: 10.1186/1471-2407-14-492.
• [20] Epigenetic profiling of gallbladder cancer and gall stone diseases: Evaluation of role of tumour associated genes.Gene. 2016 Feb 1;576(2 Pt 2):743-52. doi: 10.1016/j.gene.2015.10.004. Epub 2015 Oct 8.
• [21] Prognostic role of methylated free circulating DNA in colorectal cancer.Int J Cancer. 2012 Nov 15;131(10):2308-19. doi: 10.1002/ijc.27505. Epub 2012 Mar 27.
• [22] Human embryonic stem cell-derived test systems for developmental neurotoxicity: a transcriptomics approach. Arch Toxicol. 2013 Jan;87(1):123-43.
• [23] 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.
• [24] 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.
• [25] 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.
• [26] 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.
• [27] Comparison of phenotypic and transcriptomic effects of false-positive genotoxins, true genotoxins and non-genotoxins using HepG2 cells. Mutagenesis. 2011 Sep;26(5):593-604.
• [28] 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.
• [29] Potential advantages of DNA methyltransferase 1 (DNMT1)-targeted inhibition for cancer therapy. J Mol Med (Berl). 2007 Oct;85(10):1137-48. doi: 10.1007/s00109-007-0216-z. Epub 2007 Jun 15.
• [30] Effects of tobacco compounds on gene expression in fetal lung fibroblasts. Environ Toxicol. 2008 Aug;23(4):423-34.
• [31] Motexafin gadolinium and zinc induce oxidative stress responses and apoptosis in B-cell lymphoma lines. Cancer Res. 2005 Dec 15;65(24):11676-88.
• [32] Inhibiting ubiquitination causes an accumulation of SUMOylated newly synthesized nuclear proteins at PML bodies. J Biol Chem. 2019 Oct 18;294(42):15218-15234. doi: 10.1074/jbc.RA119.009147. Epub 2019 Jul 8.
• [33] Quantitative phosphoproteomics reveal cellular responses from caffeine, coumarin and quercetin in treated HepG2 cells. Toxicol Appl Pharmacol. 2022 Aug 15;449:116110. doi: 10.1016/j.taap.2022.116110. Epub 2022 Jun 7.
• [34] Chromatin modifiers: A new class of pollutants with potential epigenetic effects revealed by in vitro assays and transcriptomic analyses. Toxicology. 2023 Jan 15;484:153413. doi: 10.1016/j.tox.2022.153413. Epub 2022 Dec 26.