Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OT4G5SIC)

• DOT Name: Protein BEX2 (BEX2)
• Synonyms: Brain-expressed X-linked protein 2; hBex2
• Gene Name: BEX2
• Related Disease:
  Adult glioblastoma
  Advanced cancer
  Breast cancer
  Breast carcinoma
  Breast neoplasm
  Glioblastoma multiforme
  Glioma
  Hepatocellular carcinoma
  Leukemia
  Malignant glioma
  Neoplasm
  Tuberous sclerosis
  Colorectal carcinoma
  Hepatitis B virus infection
• UniProt ID: BEX2_HUMAN
• Pfam ID: PF04538
• Sequence:
  MESKEERALNNLIVENVNQENDEKDEKEQVANKGEPLALPLNVSEYCVPRGNRRRFRVRQ
  PILQYRWDIMHRLGEPQARMREENMERIGEEVRQLMEKLREKQLSHSLRAVSTDPPHHDH
  HDEFCLMP
• Function: Regulator of mitochondrial apoptosis and G1 cell cycle in breast cancer. Protects the breast cancer cells against mitochondrial apoptosis and this effect is mediated through the modulation of BCL2 protein family, which involves the positive regulation of anti-apoptotic member BCL2 and the negative regulation of pro-apoptotic members BAD, BAK1 and PUMA. Required for the normal cell cycle progression during G1 in breast cancer cells through the regulation of CCND1 and CDKN1A. Regulates the level of PP2A regulatory subunit B and PP2A phosphatase activity. 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: Expressed in central nervous system, with high level in pituitary, cerebellum and temporal lobe. Widely expressed in breast cancer cell lines.

Molecular Interaction Atlas (MIA) of This DOT

14 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Adult glioblastoma	DISVP4LU	Strong	Biomarker	[1]
Advanced cancer	DISAT1Z9	Strong	Biomarker	[1]
Breast cancer	DIS7DPX1	Strong	Biomarker	[1]
Breast carcinoma	DIS2UE88	Strong	Biomarker	[1]
Breast neoplasm	DISNGJLM	Strong	Altered Expression	[2]
Glioblastoma multiforme	DISK8246	Strong	Biomarker	[1]
Glioma	DIS5RPEH	Strong	Altered Expression	[1]
Hepatocellular carcinoma	DIS0J828	Strong	Altered Expression	[1]
Leukemia	DISNAKFL	Strong	Altered Expression	[3]
Malignant glioma	DISFXKOV	Strong	Biomarker	[4]
Neoplasm	DISZKGEW	Strong	Biomarker	[5]
Tuberous sclerosis	DISEMUGZ	moderate	Biomarker	[6]
Colorectal carcinoma	DIS5PYL0	Limited	Biomarker	[1]
Hepatitis B virus infection	DISLQ2XY	Limited	Altered Expression	[1]

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 BEX2 (BEX2).	[7]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene affects the methylation of Protein BEX2 (BEX2).	[14]

12 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 BEX2 (BEX2).	[8]
Acetaminophen	DMUIE76	Approved	Acetaminophen increases the expression of Protein BEX2 (BEX2).	[9]
Cupric Sulfate	DMP0NFQ	Approved	Cupric Sulfate decreases the expression of Protein BEX2 (BEX2).	[10]
Estradiol	DMUNTE3	Approved	Estradiol decreases the expression of Protein BEX2 (BEX2).	[11]
Temozolomide	DMKECZD	Approved	Temozolomide decreases the expression of Protein BEX2 (BEX2).	[12]
Testosterone	DM7HUNW	Approved	Testosterone decreases the expression of Protein BEX2 (BEX2).	[13]
THAPSIGARGIN	DMDMQIE	Preclinical	THAPSIGARGIN increases the expression of Protein BEX2 (BEX2).	[15]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A increases the expression of Protein BEX2 (BEX2).	[16]
Trichostatin A	DM9C8NX	Investigative	Trichostatin A decreases the expression of Protein BEX2 (BEX2).	[17]
Milchsaure	DM462BT	Investigative	Milchsaure decreases the expression of Protein BEX2 (BEX2).	[18]
Acetaldehyde	DMJFKG4	Investigative	Acetaldehyde increases the expression of Protein BEX2 (BEX2).	[19]
Hexadecanoic acid	DMWUXDZ	Investigative	Hexadecanoic acid increases the expression of Protein BEX2 (BEX2).	[20]

References

• [1] Molecular functions of brain expressed X-linked 2 (BEX2) in malignancies.Exp Cell Res. 2019 Mar 15;376(2):221-226. doi: 10.1016/j.yexcr.2019.02.014. Epub 2019 Feb 16.
• [2] A feedback loop between BEX2 and ErbB2 mediated by c-Jun signaling in breast cancer.Int J Cancer. 2012 Jan 1;130(1):71-82. doi: 10.1002/ijc.25977. Epub 2011 Apr 20.
• [3] Epigenetic regulation of brain expressed X-linked-2, a marker for acute myeloid leukemia with mixed lineage leukemia rearrangements.Leukemia. 2007 Feb;21(2):374-7. doi: 10.1038/sj.leu.2404493.
• [4] Genome-wide analysis of epigenetic silencing identifies BEX1 and BEX2 as candidate tumor suppressor genes in malignant glioma.Cancer Res. 2006 Jul 1;66(13):6665-74. doi: 10.1158/0008-5472.CAN-05-4453.
• [5] BEX2 promotes tumor proliferation in colorectal cancer.Int J Biol Sci. 2017 Feb 12;13(3):286-294. doi: 10.7150/ijbs.15171. eCollection 2017.
• [6] Brain-expressed X-linked 2 Is Pivotal for Hyperactive Mechanistic Target of Rapamycin (mTOR)-mediated Tumorigenesis.J Biol Chem. 2015 Oct 16;290(42):25756-65. doi: 10.1074/jbc.M115.665208. Epub 2015 Aug 20.
• [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] 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.
• [9] 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.
• [10] Physiological and toxicological transcriptome changes in HepG2 cells exposed to copper. Physiol Genomics. 2009 Aug 7;38(3):386-401.
• [11] Genistein and bisphenol A exposure cause estrogen receptor 1 to bind thousands of sites in a cell type-specific manner. Genome Res. 2012 Nov;22(11):2153-62.
• [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] Chemical stresses fail to mimic the unfolded protein response resulting from luminal load with unfolded polypeptides. J Biol Chem. 2018 Apr 13;293(15):5600-5612.
• [16] Genome-wide gene expression profiling of low-dose, long-term exposure of human osteosarcoma cells to bisphenol A and its analogs bisphenols AF and S. Toxicol In Vitro. 2015 Aug;29(5):1060-9.
• [17] 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.
• [18] Transcriptional profiling of lactic acid treated reconstructed human epidermis reveals pathways underlying stinging and itch. Toxicol In Vitro. 2019 Jun;57:164-173.
• [19] 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.
• [20] 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.