Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OT3LXD15)

• DOT Name: Protein BEX4 (BEX4)
• Synonyms: BEX1-like protein 1; Brain-expressed X-linked protein 4; Nerve growth factor receptor-associated protein 3
• Gene Name: BEX4
• Related Disease:
  Advanced cancer
  Neoplasm
  Oral cancer
  Squamous cell carcinoma
  Epithelial ovarian cancer
  Lung adenocarcinoma
  Ovarian cancer
  Ovarian neoplasm
  Cholestasis
  Neuroblastoma
• UniProt ID: BEX4_HUMAN
• Pfam ID: PF04538
• Sequence:
  MESKEELAANNLNGENAQQENEGGEQAPTQNEEESRHLGGGEGQKPGGNIRRGRVRRLVP
  NFRWAIPNRHIEHNEARDDVERFVGQMMEIKRKTREQQMRHYMRFQTPEPDNHYDFCLIP
• Function: May play a role in microtubule deacetylation by negatively regulating the SIRT2 deacetylase activity toward alpha-tubulin and thereby participate in the control of cell cycle progression and genomic stability. In absence of reductive stress, acts as a pseudosubstrate for the CRL2(FEM1B) complex: associates with FEM1B via zinc, thereby preventing association between FEM1B and its substrates.
• Tissue Specificity: Very high expression in heart, skeletal muscle, liver, and kidney. The levels of expression are uniform throughout the brain.

Molecular Interaction Atlas (MIA) of This DOT

10 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Advanced cancer	DISAT1Z9	Strong	Altered Expression	[1]
Neoplasm	DISZKGEW	Strong	Biomarker	[2]
Oral cancer	DISLD42D	Strong	Biomarker	[2]
Squamous cell carcinoma	DISQVIFL	Strong	Altered Expression	[2]
Epithelial ovarian cancer	DIS56MH2	moderate	Biomarker	[3]
Lung adenocarcinoma	DISD51WR	moderate	Biomarker	[4]
Ovarian cancer	DISZJHAP	moderate	Biomarker	[3]
Ovarian neoplasm	DISEAFTY	moderate	Biomarker	[3]
Cholestasis	DISDJJWE	Limited	Biomarker	[5]
Neuroblastoma	DISVZBI4	Limited	Biomarker	[6]

2 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 Protein BEX4 (BEX4).	[7]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene affects the methylation of Protein BEX4 (BEX4).	[14]

9 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 Protein BEX4 (BEX4).	[5]
Doxorubicin	DMVP5YE	Approved	Doxorubicin increases the expression of Protein BEX4 (BEX4).	[9]
Cisplatin	DMRHGI9	Approved	Cisplatin increases the expression of Protein BEX4 (BEX4).	[10]
Estradiol	DMUNTE3	Approved	Estradiol decreases the expression of Protein BEX4 (BEX4).	[11]
Temozolomide	DMKECZD	Approved	Temozolomide decreases the expression of Protein BEX4 (BEX4).	[12]
Testosterone	DM7HUNW	Approved	Testosterone decreases the expression of Protein BEX4 (BEX4).	[13]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A increases the expression of Protein BEX4 (BEX4).	[15]
Acetaldehyde	DMJFKG4	Investigative	Acetaldehyde increases the expression of Protein BEX4 (BEX4).	[16]
Hexadecanoic acid	DMWUXDZ	Investigative	Hexadecanoic acid increases the expression of Protein BEX4 (BEX4).	[17]

References

• [1] Oncogenic potential of BEX4 is conferred by Polo-like kinase 1-mediated phosphorylation.Exp Mol Med. 2018 Oct 22;50(10):1-12. doi: 10.1038/s12276-018-0168-0.
• [2] Decreased brain-expressed X-linked 4 (BEX4) expression promotes growth of oral squamous cell carcinoma.J Exp Clin Cancer Res. 2016 Jun 13;35(1):92. doi: 10.1186/s13046-016-0355-6.
• [3] Epigenetic silencing of TCEAL7 (Bex4) in ovarian cancer.Oncogene. 2005 Jul 28;24(32):5089-100. doi: 10.1038/sj.onc.1208700.
• [4] Diagnostic and prognostic value of the BEX family in lung adenocarcinoma.Oncol Lett. 2019 Nov;18(5):5523-5533. doi: 10.3892/ol.2019.10905. Epub 2019 Sep 20.
• [5] Integrative "-Omics" analysis in primary human hepatocytes unravels persistent mechanisms of cyclosporine A-induced cholestasis. Chem Res Toxicol. 2016 Dec 19;29(12):2164-2174.
• [6] Induction of Bex genes by curcumin is associated with apoptosis and activation of p53 in N2a neuroblastoma cells.Sci Rep. 2017 Feb 1;7:41420. doi: 10.1038/srep41420.
• [7] 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.
• [8] Integrative "-Omics" analysis in primary human hepatocytes unravels persistent mechanisms of cyclosporine A-induced cholestasis. Chem Res Toxicol. 2016 Dec 19;29(12):2164-2174.
• [9] 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.
• [10] Activation of AIFM2 enhances apoptosis of human lung cancer cells undergoing toxicological stress. Toxicol Lett. 2016 Sep 6;258:227-236.
• [11] 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.
• [12] 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.
• [13] 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.
• [14] Air pollution and DNA methylation alterations in lung cancer: A systematic and comparative study. Oncotarget. 2017 Jan 3;8(1):1369-1391. doi: 10.18632/oncotarget.13622.
• [15] Bisphenol A induces DSB-ATM-p53 signaling leading to cell cycle arrest, senescence, autophagy, stress response, and estrogen release in human fetal lung fibroblasts. Arch Toxicol. 2018 Apr;92(4):1453-1469.
• [16] 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.
• [17] Roles of acyl-CoA synthetase long-chain family member 5 and colony stimulating factor 2 in inhibition of palmitic or stearic acids in lung cancer cell proliferation and metabolism. Cell Biol Toxicol. 2021 Feb;37(1):15-34. doi: 10.1007/s10565-020-09520-w. Epub 2020 Apr 28.