Details of Drug Off-Target (DOT)

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

• DOT Name: Homeobox-containing protein 1 (HMBOX1)
• Synonyms: Homeobox telomere-binding protein 1; Telomere-associated homeobox-containing protein 1
• Gene Name: HMBOX1
• Related Disease:
  46,XY disorder of sex development due to testicular 17,20-desmolase deficiency
  Arteriosclerosis
  Atherosclerosis
  Cervical cancer
  Cervical carcinoma
  Epithelial ovarian cancer
  Gastric cancer
  Glioma
  Ovarian cancer
  Ovarian neoplasm
  Progressive multifocal leukoencephalopathy
  Stomach cancer
  Carcinoma of liver and intrahepatic biliary tract
  Liver cancer
  Neoplasm
• UniProt ID: HMBX1_HUMAN
• PDB ID: 2CUF; 4J19
• Pfam ID: PF04814 ; PF00046
• Sequence:
  MLSSFPVVLLETMSHYTDEPRFTIEQIDLLQRLRRTGMTKHEILHALETLDRLDQEHSDK
  FGRRSSYGGSSYGNSTNNVPASSSTATASTQTQHSGMSPSPSNSYDTSPQPCTTNQNGRE
  NNERLSTSNGKMSPTRYHANSMGQRSYSFEASEEDLDVDDKVEELMRRDSSVIKEEIKAF
  LANRRISQAVVAQVTGISQSRISHWLLQQGSDLSEQKKRAFYRWYQLEKTNPGATLSMRP
  APIPIEDPEWRQTPPPVSATSGTFRLRRGSRFTWRKECLAVMESYFNENQYPDEAKREEI
  ANACNAVIQKPGKKLSDLERVTSLKVYNWFANRRKEIKRRANIEAAILESHGIDVQSPGG
  HSNSDDVDGNDYSEQDDSTSHSDHQDPISLAVEMAAVNHTILALARQGANEIKTEALDDD
• Function: Binds directly to 5'-TTAGGG-3' repeats in telomeric DNA. Associates with the telomerase complex at sites of active telomere processing and positively regulates telomere elongation. Important for TERT binding to chromatin, indicating a role in recruitment of the telomerase complex to telomeres. Also plays a role in the alternative lengthening of telomeres (ALT) pathway in telomerase-negative cells where it promotes formation and/or maintenance of ALT-associated promyelocytic leukemia bodies (APBs). Enhances formation of telomere C-circles in ALT cells, suggesting a possible role in telomere recombination. Might also be involved in the DNA damage response at telomeres.
• Tissue Specificity: Ubiquitous. Detected in pancreas, brain, spleen, placenta, prostate, thymus, liver, heart, bone marrow, skeletal muscle, stomach, uterus, testis, kidney, ovary, colon, lung, cardiac muscle and thyroid gland.

Molecular Interaction Atlas (MIA) of This DOT

15 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
46,XY disorder of sex development due to testicular 17,20-desmolase deficiency	DISEZQMU	Strong	Altered Expression	[1]
Arteriosclerosis	DISK5QGC	Strong	Biomarker	[2]
Atherosclerosis	DISMN9J3	Strong	Biomarker	[2]
Cervical cancer	DISFSHPF	Strong	Biomarker	[3]
Cervical carcinoma	DIST4S00	Strong	Biomarker	[3]
Epithelial ovarian cancer	DIS56MH2	Strong	Altered Expression	[4]
Gastric cancer	DISXGOUK	Strong	Altered Expression	[5]
Glioma	DIS5RPEH	Strong	Biomarker	[6]
Ovarian cancer	DISZJHAP	Strong	Altered Expression	[4]
Ovarian neoplasm	DISEAFTY	Strong	Altered Expression	[4]
Progressive multifocal leukoencephalopathy	DISX02WS	Strong	Biomarker	[7]
Stomach cancer	DISKIJSX	Strong	Altered Expression	[5]
Carcinoma of liver and intrahepatic biliary tract	DIS8WA0W	Limited	Biomarker	[8]
Liver cancer	DISDE4BI	Limited	Biomarker	[8]
Neoplasm	DISZKGEW	Limited	Biomarker	[5]

10 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 Homeobox-containing protein 1 (HMBOX1).	[9]
Ciclosporin	DMAZJFX	Approved	Ciclosporin increases the expression of Homeobox-containing protein 1 (HMBOX1).	[10]
Doxorubicin	DMVP5YE	Approved	Doxorubicin decreases the expression of Homeobox-containing protein 1 (HMBOX1).	[11]
Cisplatin	DMRHGI9	Approved	Cisplatin decreases the expression of Homeobox-containing protein 1 (HMBOX1).	[12]
Temozolomide	DMKECZD	Approved	Temozolomide increases the expression of Homeobox-containing protein 1 (HMBOX1).	[13]
Vorinostat	DMWMPD4	Approved	Vorinostat decreases the expression of Homeobox-containing protein 1 (HMBOX1).	[14]
Menadione	DMSJDTY	Approved	Menadione affects the expression of Homeobox-containing protein 1 (HMBOX1).	[15]
Urethane	DM7NSI0	Phase 4	Urethane increases the expression of Homeobox-containing protein 1 (HMBOX1).	[17]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene decreases the expression of Homeobox-containing protein 1 (HMBOX1).	[18]
geraniol	DMS3CBD	Investigative	geraniol increases the expression of Homeobox-containing protein 1 (HMBOX1).	[20]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Fulvestrant	DM0YZC6	Approved	Fulvestrant increases the methylation of Homeobox-containing protein 1 (HMBOX1).	[16]
TAK-243	DM4GKV2	Phase 1	TAK-243 decreases the sumoylation of Homeobox-containing protein 1 (HMBOX1).	[19]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A increases the methylation of Homeobox-containing protein 1 (HMBOX1).	[16]

References

• [1] 5,2'-dibromo-2,4',5'-trihydroxydiphenylmethanone attenuates LPS-induced inflammation and ROS production in EA.hy926 cells via HMBOX1 induction.J Cell Mol Med. 2019 Jan;23(1):453-463. doi: 10.1111/jcmm.13948. Epub 2018 Oct 24.
• [2] Loss of HMBOX1 promotes LPS-induced apoptosis and inhibits LPS-induced autophagy of vascular endothelial cells in mouse.Apoptosis. 2019 Dec;24(11-12):946-957. doi: 10.1007/s10495-019-01572-6.
• [3] Knockdown of homeobox containing 1 increases the radiosensitivity of cervical cancer cells through telomere shortening.Oncol Rep. 2017 Jul;38(1):515-521. doi: 10.3892/or.2017.5707. Epub 2017 Jun 6.
• [4] Low expression level of HMBOX1 in high-grade serous ovarian cancer accelerates cell proliferation by inhibiting cell apoptosis.Biochem Biophys Res Commun. 2018 Jun 22;501(2):380-386. doi: 10.1016/j.bbrc.2018.04.203. Epub 2018 May 10.
• [5] High expression of HMBOX1 contributes to poor prognosis of gastric cancer by promoting cell proliferation and migration.Biomed Pharmacother. 2019 Jul;115:108867. doi: 10.1016/j.biopha.2019.108867. Epub 2019 Apr 18.
• [6] Homeoboxcontaining protein 1 loss is associated with clinicopathological performance in glioma.Mol Med Rep. 2017 Oct;16(4):4101-4106. doi: 10.3892/mmr.2017.7050. Epub 2017 Jul 21.
• [7] The telomere-associated homeobox-containing protein TAH1/HMBOX1 participates in telomere maintenance in ALT cells.J Cell Sci. 2013 Sep 1;126(Pt 17):3982-9. doi: 10.1242/jcs.128512. Epub 2013 Jun 26.
• [8] Homeobox containing1 inhibits liver cancer progression by promoting autophagy as well as inhibiting stemness and immune escape.Oncol Rep. 2018 Sep;40(3):1657-1665. doi: 10.3892/or.2018.6551. Epub 2018 Jul 10.
• [9] Human embryonic stem cell-derived test systems for developmental neurotoxicity: a transcriptomics approach. Arch Toxicol. 2013 Jan;87(1):123-43.
• [10] 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.
• [11] 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.
• [12] Low doses of cisplatin induce gene alterations, cell cycle arrest, and apoptosis in human promyelocytic leukemia cells. Biomark Insights. 2016 Aug 24;11:113-21.
• [13] 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.
• [14] 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.
• [15] Global gene expression analysis reveals differences in cellular responses to hydroxyl- and superoxide anion radical-induced oxidative stress in caco-2 cells. Toxicol Sci. 2010 Apr;114(2):193-203. doi: 10.1093/toxsci/kfp309. Epub 2009 Dec 31.
• [16] 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.
• [17] Ethyl carbamate induces cell death through its effects on multiple metabolic pathways. Chem Biol Interact. 2017 Nov 1;277:21-32.
• [18] Genome-wide transcriptional and functional analysis of human T lymphocytes treated with benzo[alpha]pyrene. Int J Mol Sci. 2018 Nov 17;19(11).
• [19] 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.
• [20] Geraniol suppresses prostate cancer growth through down-regulation of E2F8. Cancer Med. 2016 Oct;5(10):2899-2908.