Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTPO4NQV)

• DOT Name: Protein Hook homolog 2 (HOOK2)
• Synonyms: h-hook2; hHK2
• Gene Name: HOOK2
• Related Disease:
  Carcinoma of esophagus
  Esophageal cancer
  Neoplasm of esophagus
  Acute myocardial infarction
  Advanced cancer
  Aicardi-Goutieres syndrome
  Alzheimer disease
  Breast carcinoma
  Chronic obstructive pulmonary disease
  Colon cancer
  Colon carcinoma
  Esophageal squamous cell carcinoma
  Glioma
  Head and neck cancer
  Head and neck carcinoma
  Hepatitis B virus infection
  Hepatocellular carcinoma
  Neoplasm
  Non-insulin dependent diabetes
  Obesity
  Prostate carcinoma
  Carcinoma
  Aicardi-Goutieres syndrome 4
  Epithelial ovarian cancer
  Ovarian cancer
  Ovarian neoplasm
  Parkinson disease
• UniProt ID: HOOK2_HUMAN
• Pfam ID: PF05622 ; PF19047
• Sequence:
  MSVDKAELCGSLLTWLQTFHVPSPCASPQDLSSGLAVAYVLNQIDPSWFNEAWLQGISED
  PGPNWKLKVSNLKMVLRSLVEYSQDVLAHPVSEEHLPDVSLIGEFSDPAELGKLLQLVLG
  CAISCEKKQDHIQRIMTLEESVQHVVMEAIQELMTKDTPDSLSPETYGNFDSQSRRYYFL
  SEEAEEGDELQQRCLDLERQLMLLSEEKQSLAQENAGLRERMGRPEGEGTPGLTAKKLLL
  LQSQLEQLQEENFRLESGREDERLRCAELEREVAELQHRNQALTSLAQEAQALKDEMDEL
  RQSSERAGQLEATLTSCRRRLGELRELRRQVRQLEERNAGHAERTRQLEDELRRAGSLRA
  QLEAQRRQVQELQGQRQEEAMKAEKWLFECRNLEEKYESVTKEKERLLAERDSLREANEE
  LRCAQLQPRGLTQADPSLDPTSTPVDNLAAEILPAELRETLLRLQLENKRLCRQEAADRE
  RQEELQRHLEDANRARHGLETQHRLNQQQLSELRAQVEDLQKALQEQGGKTEDAISILLK
  RKLEEHLQKLHEADLELQRKREYIEELEPPTDSSTARRIEELQHNLQKKDADLRAMEERY
  RRYVDKARMVMQTMEPKQRPAAGAPPELHSLRTQLRERDVRIRHLEMDFEKSRSQREQEE
  KLLISAWYNMGMALQQRAGEERAPAHAQSFLAQQRLATNSRRGPLGRLASLNLRPTDKH
• Function: Component of the FTS/Hook/FHIP complex (FHF complex). The FHF complex may function to promote vesicle trafficking and/or fusion via the homotypic vesicular protein sorting complex (the HOPS complex). Contributes to the establishment and maintenance of centrosome function. May function in the positioning or formation of aggresomes, which are pericentriolar accumulations of misfolded proteins, proteasomes and chaperones. FHF complex promotes the distribution of AP-4 complex to the perinuclear area of the cell.

Molecular Interaction Atlas (MIA) of This DOT

27 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Carcinoma of esophagus	DISS6G4D	Definitive	Genetic Variation	[1]
Esophageal cancer	DISGB2VN	Definitive	Genetic Variation	[1]
Neoplasm of esophagus	DISOLKAQ	Definitive	Genetic Variation	[1]
Acute myocardial infarction	DISE3HTG	Strong	Altered Expression	[2]
Advanced cancer	DISAT1Z9	Strong	Biomarker	[3]
Aicardi-Goutieres syndrome	DIS1NH4X	Strong	Genetic Variation	[4]
Alzheimer disease	DISF8S70	Strong	Biomarker	[5]
Breast carcinoma	DIS2UE88	Strong	Genetic Variation	[6]
Chronic obstructive pulmonary disease	DISQCIRF	Strong	Genetic Variation	[7]
Colon cancer	DISVC52G	Strong	Biomarker	[8]
Colon carcinoma	DISJYKUO	Strong	Biomarker	[8]
Esophageal squamous cell carcinoma	DIS5N2GV	Strong	Biomarker	[9]
Glioma	DIS5RPEH	Strong	Posttranslational Modification	[10]
Head and neck cancer	DISBPSQZ	Strong	Altered Expression	[11]
Head and neck carcinoma	DISOU1DS	Strong	Altered Expression	[11]
Hepatitis B virus infection	DISLQ2XY	Strong	Altered Expression	[12]
Hepatocellular carcinoma	DIS0J828	Strong	Altered Expression	[13]
Neoplasm	DISZKGEW	Strong	Altered Expression	[3]
Non-insulin dependent diabetes	DISK1O5Z	Strong	Posttranslational Modification	[14]
Obesity	DIS47Y1K	Strong	Biomarker	[14]
Prostate carcinoma	DISMJPLE	Strong	Biomarker	[15]
Carcinoma	DISH9F1N	moderate	Altered Expression	[16]
Aicardi-Goutieres syndrome 4	DIS5GQQ1	Limited	CausalMutation	[17]
Epithelial ovarian cancer	DIS56MH2	Limited	Genetic Variation	[18]
Ovarian cancer	DISZJHAP	Limited	Genetic Variation	[18]
Ovarian neoplasm	DISEAFTY	Limited	Genetic Variation	[18]
Parkinson disease	DISQVHKL	Limited	Biomarker	[19]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Valproate	DMCFE9I	Approved	Valproate affects the expression of Protein Hook homolog 2 (HOOK2).	[20]
Ciclosporin	DMAZJFX	Approved	Ciclosporin decreases the expression of Protein Hook homolog 2 (HOOK2).	[21]
Doxorubicin	DMVP5YE	Approved	Doxorubicin increases the expression of Protein Hook homolog 2 (HOOK2).	[22]
Cupric Sulfate	DMP0NFQ	Approved	Cupric Sulfate decreases the expression of Protein Hook homolog 2 (HOOK2).	[23]
Quercetin	DM3NC4M	Approved	Quercetin increases the expression of Protein Hook homolog 2 (HOOK2).	[24]
Temozolomide	DMKECZD	Approved	Temozolomide decreases the expression of Protein Hook homolog 2 (HOOK2).	[25]
GSK2110183	DMZHB37	Phase 2	GSK2110183 increases the expression of Protein Hook homolog 2 (HOOK2).	[26]
PMID28460551-Compound-2	DM4DOUB	Patented	PMID28460551-Compound-2 decreases the expression of Protein Hook homolog 2 (HOOK2).	[28]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene affects the methylation of Protein Hook homolog 2 (HOOK2).	[27]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A decreases the methylation of Protein Hook homolog 2 (HOOK2).	[29]

References

• [1] Serological identification of tumor antigens of esophageal squamous cell carcinoma.Int J Oncol. 2005 Jan;26(1):77-86.
• [2] Human coronary thrombus formation is associated with degree of plaque disruption and expression of tissue factor and hexokinase II.Circ J. 2015;79(11):2430-8. doi: 10.1253/circj.CJ-15-0394. Epub 2015 Sep 3.
• [3] Hexokinase II and VEGF expression in liver tumors: correlation with hypoxia-inducible factor 1 alpha and its significance.J Hepatol. 2004 Jan;40(1):117-23. doi: 10.1016/s0168-8278(03)00503-8.
• [4] Synonymous mutations in RNASEH2A create cryptic splice sites impairing RNase H2 enzyme function in Aicardi-Goutires syndrome.Hum Mutat. 2013 Aug;34(8):1066-70. doi: 10.1002/humu.22336. Epub 2013 May 13.
• [5] Hook proteins: association with Alzheimer pathology and regulatory role of hook3 in amyloid beta generation.PLoS One. 2015 Mar 23;10(3):e0119423. doi: 10.1371/journal.pone.0119423. eCollection 2015.
• [6] 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.
• [7] A genome-wide analysis of the response to inhaled 2-agonists in chronic obstructive pulmonary disease.Pharmacogenomics J. 2016 Aug;16(4):326-35. doi: 10.1038/tpj.2015.65. Epub 2015 Oct 27.
• [8] Downregulation of the hexokinase II gene sensitizes human colon cancer cells to 5-fluorouracil.Chemotherapy. 2008;54(5):357-63. doi: 10.1159/000153655. Epub 2008 Sep 5.
• [9] Identification of specific and common diagnostic antibody markers for gastrointestinal cancers by SEREX screening using testis cDNA phage library.Oncotarget. 2018 Jan 1;9(26):18559-18569. doi: 10.18632/oncotarget.24963. eCollection 2018 Apr 6.
• [10] Nodal regulates energy metabolism in glioma cells by inducing expression of hypoxia-inducible factor 1.Neuro Oncol. 2013 Oct;15(10):1330-41. doi: 10.1093/neuonc/not086. Epub 2013 Aug 1.
• [11] Roles of GLUT-1 and HK-II expression in the biological behavior of head and neck cancer.Oncotarget. 2019 Apr 30;10(32):3066-3083. doi: 10.18632/oncotarget.24684. eCollection 2019 Apr 30.
• [12] Differential association of STAT3 and HK-II expression in hepatitis B virus- and hepatitis C virus-related hepatocellular carcinoma.J Med Virol. 2016 Sep;88(9):1552-9. doi: 10.1002/jmv.24498. Epub 2016 Mar 8.
• [13] Hexokinase-II Inhibition Synergistically Augments the Anti-tumor Efficacy of Sorafenib in Hepatocellular Carcinoma.Int J Mol Sci. 2019 Mar 14;20(6):1292. doi: 10.3390/ijms20061292.
• [14] Altered intragenic DNA methylation of HOOK2 gene in adipose tissue from individuals with obesity and type 2 diabetes.PLoS One. 2017 Dec 11;12(12):e0189153. doi: 10.1371/journal.pone.0189153. eCollection 2017.
• [15] Comparison of human prostate specific glandular kallikrein 2 and prostate specific antigen gene expression in prostate with gene amplification and overexpression of prostate specific glandular kallikrein 2 in tumor tissue.Cancer. 2001 Dec 15;92(12):2975-84. doi: 10.1002/1097-0142(20011215)92:12<2975::aid-cncr10113>3.0.co;2-k.
• [16] Warburg effect, hexokinase-II, and radioresistance of laryngeal carcinoma.Oncotarget. 2017 Feb 21;8(8):14133-14146. doi: 10.18632/oncotarget.13044.
• [17] Assessment of interferon-related biomarkers in Aicardi-Goutires syndrome associated with mutations in TREX1, RNASEH2A, RNASEH2B, RNASEH2C, SAMHD1, and ADAR: a case-control study.Lancet Neurol. 2013 Dec;12(12):1159-69. doi: 10.1016/S1474-4422(13)70258-8. Epub 2013 Oct 30.
• [18] Frequent translocations of 11q13.2 and 19p13.2 in ovarian cancer.Genes Chromosomes Cancer. 2014 Jun;53(6):447-53. doi: 10.1002/gcc.22152. Epub 2014 Feb 24.
• [19] TIGAR inclusion pathology is specific for Lewy body diseases.Brain Res. 2019 Mar 1;1706:218-223. doi: 10.1016/j.brainres.2018.09.032. Epub 2018 Sep 26.
• [20] 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.
• [21] Integrating multiple omics to unravel mechanisms of Cyclosporin A induced hepatotoxicity in vitro. Toxicol In Vitro. 2015 Apr;29(3):489-501.
• [22] 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.
• [23] Physiological and toxicological transcriptome changes in HepG2 cells exposed to copper. Physiol Genomics. 2009 Aug 7;38(3):386-401.
• [24] Protein expression profiling identifies molecular targets of quercetin as a major dietary flavonoid in human colon cancer cells. Proteomics. 2004 Jul;4(7):2160-74.
• [25] Temozolomide induces activation of Wnt/-catenin signaling in glioma cells via PI3K/Akt pathway: implications in glioma therapy. Cell Biol Toxicol. 2020 Jun;36(3):273-278. doi: 10.1007/s10565-019-09502-7. Epub 2019 Nov 22.
• [26] Novel ATP-competitive Akt inhibitor afuresertib suppresses the proliferation of malignant pleural mesothelioma cells. Cancer Med. 2017 Nov;6(11):2646-2659. doi: 10.1002/cam4.1179. Epub 2017 Sep 27.
• [27] Effect of aflatoxin B(1), benzo[a]pyrene, and methapyrilene on transcriptomic and epigenetic alterations in human liver HepaRG cells. Food Chem Toxicol. 2018 Nov;121:214-223. doi: 10.1016/j.fct.2018.08.034. Epub 2018 Aug 26.
• [28] 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.
• [29] 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.