Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTOQ5WS4)

• DOT Name: Chromobox protein homolog 2 (CBX2)
• Gene Name: CBX2
• Related Disease:
  Bone osteosarcoma
  Castration-resistant prostate carcinoma
  Osteosarcoma
  Prostate cancer
  Prostate carcinoma
  Breast neoplasm
  Chromosomal disorder
  Epithelial ovarian cancer
  Gonadal disorder
  Lung neoplasm
  Neoplasm
  Ovarian cancer
  Ovarian neoplasm
  46,XY disorder of sex development
  Hepatocellular carcinoma
  Polycystic ovarian syndrome
  46,XY complete gonadal dysgenesis
  46,XY sex reversal 5
  Advanced cancer
  Breast cancer
  Breast carcinoma
  Female hypogonadism
  Invasive breast carcinoma
  leukaemia
  Leukemia
• UniProt ID: CBX2_HUMAN
• PDB ID: 2D9U; 3H91; 5EPK
• Pfam ID: PF17218 ; PF00385
• Sequence:
  MEELSSVGEQVFAAECILSKRLRKGKLEYLVKWRGWSSKHNSWEPEENILDPRLLLAFQK
  KEHEKEVQNRKRGKRPRGRPRKLTAMSSCSRRSKLKEPDAPSKSKSSSSSSSSTSSSSSS
  DEEDDSDLDAKRGPRGRETHPVPQKKAQILVAKPELKDPIRKKRGRKPLPPEQKATRRPV
  SLAKVLKTARKDLGAPASKLPPPLSAPVAGLAALKAHAKEACGGPSAMATPENLASLMKG
  MASSPGRGGISWQSSIVHYMNRMTQSQAQAASRLALKAQATNKCGLGLDLKVRTQKGELG
  MSPPGSKIPKAPSGGAVEQKVGNTGGPPHTHGASRVPAGCPGPQPAPTQELSLQVLDLQS
  VKNGMPGVGLLARHATATKGVPATNPAPGKGTGSGLIGASGATMPTDTSKSEKLASRAVA
  PPTPASKRDCVKGSATPSGQESRTAPGEARKAATLPEMSAGEESSSSDSDPDSASPPSTG
  QNPSVSVQTSQDWKPTRSLIEHVFVTDVTANLITVTVKESPTSVGFFNLRHY
• Function: Component of a Polycomb group (PcG) multiprotein PRC1-like complex, a complex class required to maintain the transcriptionally repressive state of many genes, including Hox genes, throughout development. PcG PRC1 complex acts via chromatin remodeling and modification of histones; it mediates monoubiquitination of histone H2A 'Lys-119', rendering chromatin heritably changed in its expressibility. Binds to histone H3 trimethylated at 'Lys-9' (H3K9me3) or at 'Lys-27' (H3K27me3). Plays a role in the lineage differentiation of the germ layers in embryonic development. Involved in sexual development, acting as activator of NR5A1 expression.
• KEGG Pathway: Polycomb repressive complex (hsa03083)
• Reactome Pathway:
  SUMOylation of DNA damage response and repair proteins (R-HSA-3108214)
  SUMOylation of transcription cofactors (R-HSA-3899300)
  SUMOylation of chromatin organization proteins (R-HSA-4551638)
  SUMOylation of RNA binding proteins (R-HSA-4570464)
  SUMOylation of DNA methylation proteins (R-HSA-4655427)
  RUNX1 interacts with co-factors whose precise effect on RUNX1 targets is not known (R-HSA-8939243)
  Regulation of PTEN gene transcription (R-HSA-8943724)
  Oxidative Stress Induced Senescence (R-HSA-2559580)

Molecular Interaction Atlas (MIA) of This DOT

25 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Bone osteosarcoma	DIST1004	Definitive	Biomarker	[1]
Castration-resistant prostate carcinoma	DISVGAE6	Definitive	Biomarker	[2]
Osteosarcoma	DISLQ7E2	Definitive	Biomarker	[1]
Prostate cancer	DISF190Y	Definitive	Biomarker	[2]
Prostate carcinoma	DISMJPLE	Definitive	Biomarker	[2]
Breast neoplasm	DISNGJLM	Strong	Altered Expression	[3]
Chromosomal disorder	DISM5BB5	Strong	Genetic Variation	[4]
Epithelial ovarian cancer	DIS56MH2	Strong	Biomarker	[5]
Gonadal disorder	DIS4HEW4	Strong	Biomarker	[6]
Lung neoplasm	DISVARNB	Strong	Biomarker	[4]
Neoplasm	DISZKGEW	Strong	Biomarker	[1]
Ovarian cancer	DISZJHAP	Strong	Biomarker	[5]
Ovarian neoplasm	DISEAFTY	Strong	Biomarker	[5]
46,XY disorder of sex development	DIS78CGG	moderate	Genetic Variation	[7]
Hepatocellular carcinoma	DIS0J828	moderate	Biomarker	[8]
Polycystic ovarian syndrome	DISZ2BNG	moderate	Biomarker	[9]
46,XY complete gonadal dysgenesis	DISLF3LT	Supportive	Autosomal dominant	[10]
46,XY sex reversal 5	DISY84HV	Limited	Semidominant	[11]
Advanced cancer	DISAT1Z9	Limited	Altered Expression	[12]
Breast cancer	DIS7DPX1	Limited	Biomarker	[3]
Breast carcinoma	DIS2UE88	Limited	Biomarker	[3]
Female hypogonadism	DISWASB4	Limited	Biomarker	[9]
Invasive breast carcinoma	DISANYTW	Limited	Biomarker	[3]
leukaemia	DISS7D1V	Limited	Biomarker	[13]
Leukemia	DISNAKFL	Limited	Biomarker	[13]

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 Chromobox protein homolog 2 (CBX2).	[14]
TAK-243	DM4GKV2	Phase 1	TAK-243 increases the sumoylation of Chromobox protein homolog 2 (CBX2).	[27]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Tretinoin	DM49DUI	Approved	Tretinoin decreases the expression of Chromobox protein homolog 2 (CBX2).	[15]
Acetaminophen	DMUIE76	Approved	Acetaminophen increases the expression of Chromobox protein homolog 2 (CBX2).	[16]
Cisplatin	DMRHGI9	Approved	Cisplatin increases the expression of Chromobox protein homolog 2 (CBX2).	[17]
Estradiol	DMUNTE3	Approved	Estradiol increases the expression of Chromobox protein homolog 2 (CBX2).	[18]
Quercetin	DM3NC4M	Approved	Quercetin decreases the expression of Chromobox protein homolog 2 (CBX2).	[19]
Temozolomide	DMKECZD	Approved	Temozolomide increases the expression of Chromobox protein homolog 2 (CBX2).	[20]
Calcitriol	DM8ZVJ7	Approved	Calcitriol decreases the expression of Chromobox protein homolog 2 (CBX2).	[21]
Testosterone	DM7HUNW	Approved	Testosterone decreases the expression of Chromobox protein homolog 2 (CBX2).	[22]
Carbamazepine	DMZOLBI	Approved	Carbamazepine affects the expression of Chromobox protein homolog 2 (CBX2).	[23]
Methotrexate	DM2TEOL	Approved	Methotrexate increases the expression of Chromobox protein homolog 2 (CBX2).	[24]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene increases the expression of Chromobox protein homolog 2 (CBX2).	[25]
Leflunomide	DMR8ONJ	Phase 1 Trial	Leflunomide decreases the expression of Chromobox protein homolog 2 (CBX2).	[26]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A increases the expression of Chromobox protein homolog 2 (CBX2).	[28]
Trichostatin A	DM9C8NX	Investigative	Trichostatin A decreases the expression of Chromobox protein homolog 2 (CBX2).	[29]

References

• [1] CBX2 is a functional target of miRNA let-7a and acts as a tumor promoter in osteosarcoma.Cancer Med. 2019 Jul;8(8):3981-3991. doi: 10.1002/cam4.2320. Epub 2019 May 31.
• [2] Identification of the epigenetic reader CBX2 as a potential drug target in advanced prostate cancer.Clin Epigenetics. 2016 Feb 12;8:16. doi: 10.1186/s13148-016-0182-9. eCollection 2016.
• [3] A novel approach to modelling transcriptional heterogeneity identifies the oncogene candidate CBX2 in invasive breast carcinoma.Br J Cancer. 2019 Apr;120(7):746-753. doi: 10.1038/s41416-019-0387-8. Epub 2019 Mar 1.
• [4] Genotranscriptomic meta-analysis of the Polycomb gene CBX2 in human cancers: initial evidence of an oncogenic role.Br J Cancer. 2014 Oct 14;111(8):1663-72. doi: 10.1038/bjc.2014.474. Epub 2014 Sep 16.
• [5] CBX2 identified as driver of anoikis escape and dissemination in high grade serous ovarian cancer.Oncogenesis. 2018 Nov 26;7(11):92. doi: 10.1038/s41389-018-0103-1.
• [6] CBX2 gene analysis in patients with 46,XY and 46,XX gonadal disorders of sex development.Fertil Steril. 2013 Mar 1;99(3):819-826.e3. doi: 10.1016/j.fertnstert.2012.11.016. Epub 2012 Dec 7.
• [7] Assembling the jigsaw puzzle: CBX2 isoform 2 and its targets in disorders/differences of sex development.Mol Genet Genomic Med. 2018 Sep;6(5):785-795. doi: 10.1002/mgg3.445. Epub 2018 Jul 11.
• [8] Integrated analysis of competing endogenous RNA network revealing potential prognostic biomarkers of hepatocellular carcinoma.J Cancer. 2019 Jun 2;10(14):3267-3283. doi: 10.7150/jca.29986. eCollection 2019.
• [9] The transcriptional regulator CBX2 and ovarian function: A whole genome and whole transcriptome approach.Sci Rep. 2019 Nov 19;9(1):17033. doi: 10.1038/s41598-019-53370-4.
• [10] Ovaries and female phenotype in a girl with 46,XY karyotype and mutations in the CBX2 gene. Am J Hum Genet. 2009 May;84(5):658-63. doi: 10.1016/j.ajhg.2009.03.016. Epub 2009 Apr 9.
• [11] Classification of Genes: Standardized Clinical Validity Assessment of Gene-Disease Associations Aids Diagnostic Exome Analysis and Reclassifications. Hum Mutat. 2017 May;38(5):600-608. doi: 10.1002/humu.23183. Epub 2017 Feb 13.
• [12] Beyond EZH2: is the polycomb protein CBX2 an emerging target for anti-cancer therapy?.Expert Opin Ther Targets. 2019 Jul;23(7):565-578. doi: 10.1080/14728222.2019.1627329. Epub 2019 Jun 10.
• [13] The HDAC inhibitor SAHA regulates CBX2 stability via a SUMO-triggered ubiquitin-mediated pathway in leukemia.Oncogene. 2018 May;37(19):2559-2572. doi: 10.1038/s41388-018-0143-1. Epub 2018 Feb 22.
• [14] 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.
• [15] Development of a neural teratogenicity test based on human embryonic stem cells: response to retinoic acid exposure. Toxicol Sci. 2011 Dec;124(2):370-7.
• [16] Multiple microRNAs function as self-protective modules in acetaminophen-induced hepatotoxicity in humans. Arch Toxicol. 2018 Feb;92(2):845-858.
• [17] 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.
• [18] 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.
• [19] Quantitative proteomic analysis of HepG2 cells treated with quercetin suggests IQGAP1 involved in quercetin-induced regulation of cell proliferation and migration. OMICS. 2009 Apr;13(2):93-103. doi: 10.1089/omi.2008.0075.
• [20] 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.
• [21] Large-scale in silico and microarray-based identification of direct 1,25-dihydroxyvitamin D3 target genes. Mol Endocrinol. 2005 Nov;19(11):2685-95.
• [22] Effects of 1alpha,25 dihydroxyvitamin D3 and testosterone on miRNA and mRNA expression in LNCaP cells. Mol Cancer. 2011 May 18;10:58.
• [23] 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.
• [24] Global molecular effects of tocilizumab therapy in rheumatoid arthritis synovium. Arthritis Rheumatol. 2014 Jan;66(1):15-23.
• [25] Identification of a transcriptomic signature of food-relevant genotoxins in human HepaRG hepatocarcinoma cells. Food Chem Toxicol. 2020 Jun;140:111297. doi: 10.1016/j.fct.2020.111297. Epub 2020 Mar 28.
• [26] Endoplasmic reticulum stress and MAPK signaling pathway activation underlie leflunomide-induced toxicity in HepG2 Cells. Toxicology. 2017 Dec 1;392:11-21.
• [27] 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.
• [28] Bisphenol A and bisphenol S induce distinct transcriptional profiles in differentiating human primary preadipocytes. PLoS One. 2016 Sep 29;11(9):e0163318.
• [29] From transient transcriptome responses to disturbed neurodevelopment: role of histone acetylation and methylation as epigenetic switch between reversible and irreversible drug effects. Arch Toxicol. 2014 Jul;88(7):1451-68.