Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTOP9RLD)

• DOT Name: Chromobox protein homolog 3 (CBX3)
• Synonyms: HECH; Heterochromatin protein 1 homolog gamma; HP1 gamma; Modifier 2 protein
• Gene Name: CBX3
• Related Disease:
  Carcinoma of liver and intrahepatic biliary tract
  Hepatocellular carcinoma
  Liver cancer
  Advanced cancer
  Bone osteosarcoma
  Breast carcinoma
  Colon cancer
  Colon carcinoma
  Colorectal carcinoma
  Dedifferentiated liposarcoma
  Dyskeratosis congenita
  Glioma
  Haematological malignancy
  Inflammatory bowel disease
  Malignant soft tissue neoplasm
  Myeloid leukaemia
  Neoplasm
  Non-small-cell lung cancer
  Osteosarcoma
  Pancreatic adenocarcinoma
  Pleomorphic sarcoma
  Sarcoma
  Seminoma
  Teratoma
  Lung adenocarcinoma
  Pancreatic cancer
  Prostate cancer
  Prostate carcinoma
  Triple negative breast cancer
  Adult glioblastoma
  Glioblastoma multiforme
  Breast cancer
  Sickle-cell anaemia
• UniProt ID: CBX3_HUMAN
• PDB ID: 2L11; 3DM1; 3KUP; 3TZD; 5T1I; 6HW2
• Pfam ID: PF00385 ; PF01393
• Sequence:
  MASNKTTLQKMGKKQNGKSKKVEEAEPEEFVVEKVLDRRVVNGKVEYFLKWKGFTDADNT
  WEPEENLDCPELIEAFLNSQKAGKEKDGTKRKSLSDSESDDSKSKKKRDAADKPRGFARG
  LDPERIIGATDSSGELMFLMKWKDSDEADLVLAKEANMKCPQIVIAFYEERLTWHSCPED
  EAQ
• Function: Seems to be involved in transcriptional silencing in heterochromatin-like complexes. Recognizes and binds histone H3 tails methylated at 'Lys-9', leading to epigenetic repression. May contribute to the association of the heterochromatin with the inner nuclear membrane through its interaction with lamin B receptor (LBR). Involved in the formation of functional kinetochore through interaction with MIS12 complex proteins. Contributes to the conversion of local chromatin to a heterochromatin-like repressive state through H3 'Lys-9' trimethylation, mediates the recruitment of the methyltransferases SUV39H1 and/or SUV39H2 by the PER complex to the E-box elements of the circadian target genes such as PER2 itself or PER1. Mediates the recruitment of NIPBL to sites of DNA damage at double-strand breaks (DSBs).
• KEGG Pathway:
  Polycomb repressive complex (hsa03083)
  Shigellosis (hsa05131)
• Reactome Pathway:
  RNA Polymerase I Promoter Escape (R-HSA-73772)
  Transcriptional Regulation by E2F6 (R-HSA-8953750)
  ERCC6 (CSB) and EHMT2 (G9a) positively regulate rRNA expression (R-HSA-427389)

Molecular Interaction Atlas (MIA) of This DOT

33 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Carcinoma of liver and intrahepatic biliary tract	DIS8WA0W	Definitive	Biomarker	[1]
Hepatocellular carcinoma	DIS0J828	Definitive	Altered Expression	[1]
Liver cancer	DISDE4BI	Definitive	Biomarker	[1]
Advanced cancer	DISAT1Z9	Strong	Biomarker	[2]
Bone osteosarcoma	DIST1004	Strong	Altered Expression	[2]
Breast carcinoma	DIS2UE88	Strong	Altered Expression	[3]
Colon cancer	DISVC52G	Strong	Biomarker	[4]
Colon carcinoma	DISJYKUO	Strong	Biomarker	[4]
Colorectal carcinoma	DIS5PYL0	Strong	Biomarker	[5]
Dedifferentiated liposarcoma	DISYJUCJ	Strong	Altered Expression	[2]
Dyskeratosis congenita	DISSXV0K	Strong	Biomarker	[6]
Glioma	DIS5RPEH	Strong	Altered Expression	[7]
Haematological malignancy	DISCDP7W	Strong	Biomarker	[8]
Inflammatory bowel disease	DISGN23E	Strong	Biomarker	[9]
Malignant soft tissue neoplasm	DISTC6NO	Strong	Altered Expression	[2]
Myeloid leukaemia	DISMN944	Strong	Altered Expression	[10]
Neoplasm	DISZKGEW	Strong	Altered Expression	[11]
Non-small-cell lung cancer	DIS5Y6R9	Strong	Altered Expression	[12]
Osteosarcoma	DISLQ7E2	Strong	Altered Expression	[2]
Pancreatic adenocarcinoma	DISKHX7S	Strong	Biomarker	[13]
Pleomorphic sarcoma	DISXU8CC	Strong	Altered Expression	[2]
Sarcoma	DISZDG3U	Strong	Altered Expression	[2]
Seminoma	DIS3J8LJ	Strong	Altered Expression	[14]
Teratoma	DIS6ICY4	Strong	Altered Expression	[14]
Lung adenocarcinoma	DISD51WR	moderate	Altered Expression	[15]
Pancreatic cancer	DISJC981	moderate	Biomarker	[16]
Prostate cancer	DISF190Y	moderate	Biomarker	[17]
Prostate carcinoma	DISMJPLE	moderate	Biomarker	[17]
Triple negative breast cancer	DISAMG6N	moderate	Altered Expression	[3]
Adult glioblastoma	DISVP4LU	Disputed	Altered Expression	[18]
Glioblastoma multiforme	DISK8246	Disputed	Altered Expression	[18]
Breast cancer	DIS7DPX1	Limited	Altered Expression	[19]
Sickle-cell anaemia	DIS5YNZB	Limited	Altered Expression	[20]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Valproate	DMCFE9I	Approved	Valproate decreases the methylation of Chromobox protein homolog 3 (CBX3).	[21]
TAK-243	DM4GKV2	Phase 1	TAK-243 affects the sumoylation of Chromobox protein homolog 3 (CBX3).	[33]
Hexadecanoic acid	DMWUXDZ	Investigative	Hexadecanoic acid decreases the phosphorylation of Chromobox protein homolog 3 (CBX3).	[35]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Ciclosporin	DMAZJFX	Approved	Ciclosporin decreases the expression of Chromobox protein homolog 3 (CBX3).	[22]
Tretinoin	DM49DUI	Approved	Tretinoin decreases the expression of Chromobox protein homolog 3 (CBX3).	[23]
Doxorubicin	DMVP5YE	Approved	Doxorubicin decreases the expression of Chromobox protein homolog 3 (CBX3).	[24]
Cupric Sulfate	DMP0NFQ	Approved	Cupric Sulfate decreases the expression of Chromobox protein homolog 3 (CBX3).	[25]
Ivermectin	DMDBX5F	Approved	Ivermectin decreases the expression of Chromobox protein homolog 3 (CBX3).	[26]
Hydrogen peroxide	DM1NG5W	Approved	Hydrogen peroxide affects the expression of Chromobox protein homolog 3 (CBX3).	[27]
Vorinostat	DMWMPD4	Approved	Vorinostat increases the expression of Chromobox protein homolog 3 (CBX3).	[28]
Demecolcine	DMCZQGK	Approved	Demecolcine decreases the expression of Chromobox protein homolog 3 (CBX3).	[29]
Isotretinoin	DM4QTBN	Approved	Isotretinoin decreases the expression of Chromobox protein homolog 3 (CBX3).	[23]
Bortezomib	DMNO38U	Approved	Bortezomib increases the expression of Chromobox protein homolog 3 (CBX3).	[30]
Nicotine	DMWX5CO	Approved	Nicotine increases the expression of Chromobox protein homolog 3 (CBX3).	[31]
Alitretinoin	DMME8LH	Approved	Alitretinoin decreases the expression of Chromobox protein homolog 3 (CBX3).	[23]
Tamibarotene	DM3G74J	Phase 3	Tamibarotene affects the expression of Chromobox protein homolog 3 (CBX3).	[32]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A affects the expression of Chromobox protein homolog 3 (CBX3).	[34]
Formaldehyde	DM7Q6M0	Investigative	Formaldehyde decreases the expression of Chromobox protein homolog 3 (CBX3).	[29]
all-trans-4-oxo-retinoic acid	DMM2R1N	Investigative	all-trans-4-oxo-retinoic acid decreases the expression of Chromobox protein homolog 3 (CBX3).	[23]
9-hydroxyoctadecadienoic acid	DM0FWNJ	Investigative	9-hydroxyoctadecadienoic acid decreases the expression of Chromobox protein homolog 3 (CBX3).	[36]

References

• [1] CBX3/HP1 promotes tumor proliferation and predicts poor survival in hepatocellular carcinoma.Aging (Albany NY). 2019 Aug 2;11(15):5483-5497. doi: 10.18632/aging.102132. Epub 2019 Aug 2.
• [2] CBX3 predicts an unfavorable prognosis and promotes tumorigenesis in osteosarcoma.Mol Med Rep. 2019 May;19(5):4205-4212. doi: 10.3892/mmr.2019.10104. Epub 2019 Mar 28.
• [3] KDM2A-dependent reduction of rRNA transcription on glucose starvation requires HP1 in cells, including triple-negative breast cancer cells.Oncotarget. 2019 Jul 30;10(46):4743-4760. doi: 10.18632/oncotarget.27092. eCollection 2019 Jul 30.
• [4] CBX3 promotes colon cancer cell proliferation by CDK6 kinase-independent function during cell cycle.Oncotarget. 2017 Mar 21;8(12):19934-19946. doi: 10.18632/oncotarget.15253.
• [5] Heterochromatin protein HP1 promotes colorectal cancer progression and is regulated by miR-30a.Cancer Res. 2015 Nov 1;75(21):4593-604. doi: 10.1158/0008-5472.CAN-14-3735. Epub 2015 Sep 2.
• [6] A role for heterochromatin protein 1 at human telomeres.Genes Dev. 2011 Sep 1;25(17):1807-19. doi: 10.1101/gad.17325211. Epub 2011 Aug 24.
• [7] Circ-EZH2 knockdown reverses DDAH1 and CBX3-mediated cell growth and invasion in glioma through miR-1265 sponge activity.Gene. 2020 Feb 5;726:144196. doi: 10.1016/j.gene.2019.144196. Epub 2019 Oct 26.
• [8] Chromatin Regulation by HP1 Contributes to Survival of 5-Azacytidine-Resistant Cells.Front Pharmacol. 2018 Oct 16;9:1166. doi: 10.3389/fphar.2018.01166. eCollection 2018.
• [9] Macrophages, nitric oxide and microRNAs are associated with DNA damage response pathway and senescence in inflammatory bowel disease.PLoS One. 2012;7(9):e44156. doi: 10.1371/journal.pone.0044156. Epub 2012 Sep 6.
• [10] Granulocyte maturation determines ability to release chromatin NETs and loss of DNA damage response; these properties are absent in immature AML granulocytes.Biochim Biophys Acta. 2013 Mar;1833(3):767-79. doi: 10.1016/j.bbamcr.2012.12.012. Epub 2012 Dec 23.
• [11] CBX3 promotes glioma U87 cell proliferation and predicts an unfavorable prognosis.J Neurooncol. 2019 Oct;145(1):35-48. doi: 10.1007/s11060-019-03286-w. Epub 2019 Sep 9.
• [12] CBX3/heterochromatin protein 1 gamma is significantly upregulated in patients with non-small cell lung cancer.Asia Pac J Clin Oncol. 2018 Oct;14(5):e283-e288. doi: 10.1111/ajco.12820. Epub 2017 Nov 10.
• [13] Overexpression of CBX3 in Pancreatic Adenocarcinoma Promotes Cell Cycle Transition-Associated Tumor Progression.Int J Mol Sci. 2018 Jun 14;19(6):1768. doi: 10.3390/ijms19061768.
• [14] Heterochromatin marks HP1, HP1 and H3K9me3, and DNA damage response activation in human testis development and germ cell tumours.Int J Androl. 2011 Aug;34(4 Pt 2):e103-13. doi: 10.1111/j.1365-2605.2010.01096.x. Epub 2010 Aug 1.
• [15] HP1 Promotes Lung Adenocarcinoma by Downregulating the Transcription-Repressive Regulators NCOR2 and ZBTB7A.Cancer Res. 2018 Jul 15;78(14):3834-3848. doi: 10.1158/0008-5472.CAN-17-3571. Epub 2018 May 15.
• [16] CBX3 promotes proliferation and regulates glycolysis via suppressing FBP1 in pancreatic cancer.Biochem Biophys Res Commun. 2018 Jun 7;500(3):691-697. doi: 10.1016/j.bbrc.2018.04.137. Epub 2018 Apr 22.
• [17] A regulatory circuit HP1/miR-451a/c-Myc promotes prostate cancer progression.Oncogene. 2018 Jan 25;37(4):415-426. doi: 10.1038/onc.2017.332. Epub 2017 Oct 2.
• [18] Integrated analysis of 34 microarray datasets reveals CBX3 as a diagnostic and prognostic biomarker in glioblastoma.J Transl Med. 2019 May 28;17(1):179. doi: 10.1186/s12967-019-1930-3.
• [19] Prognostic values of distinct CBX family members in breast cancer.Oncotarget. 2017 Sep 28;8(54):92375-92387. doi: 10.18632/oncotarget.21325. eCollection 2017 Nov 3.
• [20] Heterochromatin Protein 1 Is a Novel Epigenetic Repressor of Human Embryonic -Globin Gene Expression.J Biol Chem. 2017 Mar 24;292(12):4811-4817. doi: 10.1074/jbc.M116.768515. Epub 2017 Feb 1.
• [21] 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.
• [22] Integrating multiple omics to unravel mechanisms of Cyclosporin A induced hepatotoxicity in vitro. Toxicol In Vitro. 2015 Apr;29(3):489-501.
• [23] Retinoic acid and its 4-oxo metabolites are functionally active in human skin cells in vitro. J Invest Dermatol. 2005 Jul;125(1):143-53.
• [24] 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.
• [25] Physiological and toxicological transcriptome changes in HepG2 cells exposed to copper. Physiol Genomics. 2009 Aug 7;38(3):386-401.
• [26] Quantitative proteomics reveals a broad-spectrum antiviral property of ivermectin, benefiting for COVID-19 treatment. J Cell Physiol. 2021 Apr;236(4):2959-2975. doi: 10.1002/jcp.30055. Epub 2020 Sep 22.
• [27] Minimal peroxide exposure of neuronal cells induces multifaceted adaptive responses. PLoS One. 2010 Dec 17;5(12):e14352. doi: 10.1371/journal.pone.0014352.
• [28] 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.
• [29] Characterization of formaldehyde's genotoxic mode of action by gene expression analysis in TK6 cells. Arch Toxicol. 2013 Nov;87(11):1999-2012.
• [30] The proapoptotic effect of zoledronic acid is independent of either the bone microenvironment or the intrinsic resistance to bortezomib of myeloma cells and is enhanced by the combination with arsenic trioxide. Exp Hematol. 2011 Jan;39(1):55-65.
• [31] Nicotinic modulation of gene expression in SH-SY5Y neuroblastoma cells. Brain Res. 2006 Oct 20;1116(1):39-49.
• [32] Differential modulation of PI3-kinase/Akt pathway during all-trans retinoic acid- and Am80-induced HL-60 cell differentiation revealed by DNA microarray analysis. Biochem Pharmacol. 2004 Dec 1;68(11):2177-86.
• [33] 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.
• [34] Comprehensive analysis of transcriptomic changes induced by low and high doses of bisphenol A in HepG2 spheroids in vitro and rat liver in vivo. Environ Res. 2019 Jun;173:124-134. doi: 10.1016/j.envres.2019.03.035. Epub 2019 Mar 18.
• [35] Functional lipidomics: Palmitic acid impairs hepatocellular carcinoma development by modulating membrane fluidity and glucose metabolism. Hepatology. 2017 Aug;66(2):432-448. doi: 10.1002/hep.29033. Epub 2017 Jun 16.
• [36] A proteomic analysis of acute leukemia cells treated with 9-hydroxyoctadecadienoic acid. Lipids Health Dis. 2016 Nov 10;15(1):192. doi: 10.1186/s12944-016-0359-4.