Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTLUDG5T)

• DOT Name: Cell cycle and apoptosis regulator protein 2 (CCAR2)
• Synonyms: Cell division cycle and apoptosis regulator protein 2; DBIRD complex subunit KIAA1967; Deleted in breast cancer gene 1 protein; DBC-1; DBC.1; NET35; p30 DBC
• Gene Name: CCAR2
• Related Disease:
  Lung adenocarcinoma
  Lung squamous cell carcinoma
  Acute lymphocytic leukaemia
  Aerodigestive tract cancer
  Arteriosclerosis
  Atherosclerosis
  Bladder cancer
  Breast cancer
  Breast carcinoma
  Breast neoplasm
  Colorectal adenoma
  Colorectal carcinoma
  Esophageal squamous cell carcinoma
  Fatty liver disease
  Malignant soft tissue neoplasm
  Matthew-Wood syndrome
  Neoplasm
  Neuroblastoma
  Obesity
  Prostate cancer
  Prostate carcinoma
  Sarcoma
  Soft tissue sarcoma
  Squamous cell carcinoma
  Stomach cancer
  Transitional cell carcinoma
  Urinary bladder cancer
  Urinary bladder neoplasm
  Urothelial carcinoma
  Carcinoma
  Colon cancer
  Colon carcinoma
  Hepatocellular carcinoma
  Lung cancer
  Castration-resistant prostate carcinoma
  Gastric cancer
  Myasthenia gravis
  Non-insulin dependent diabetes
• UniProt ID: CCAR2_HUMAN
• Pfam ID: PF19257 ; PF14443 ; PF19256 ; PF14444
• Sequence:
  MSQFKRQRINPLPGGRNFSGTASTSLLGPPPGLLTPPVATELSQNARHLQGGEKQRVFTG
  IVTSLHDYFGVVDEEVFFQLSVVKGRLPQLGEKVLVKAAYNPGQAVPWNAVKVQTLSNQP
  LLKSPAPPLLHVAALGQKQGILGAQPQLIFQPHRIPPLFPQKPLSLFQTSHTLHLSHLNR
  FPARGPHGRLDQGRSDDYDSKKRKQRAGGEPWGAKKPRHDLPPYRVHLTPYTVDSPICDF
  LELQRRYRSLLVPSDFLSVHLSWLSAFPLSQPFSLHHPSRIQVSSEKEAAPDAGAEPITA
  DSDPAYSSKVLLLSSPGLEELYRCCMLFVDDMAEPRETPEHPLKQIKFLLGRKEEEAVLV
  GGEWSPSLDGLDPQADPQVLVRTAIRCAQAQTGIDLSGCTKWWRFAEFQYLQPGPPRRLQ
  TVVVYLPDVWTIMPTLEEWEALCQQKAAEAAPPTQEAQGETEPTEQAPDALEQAADTSRR
  NAETPEATTQQETDTDLPEAPPPPLEPAVIARPGCVNLSLHGIVEDRRPKERISFEVMVL
  AELFLEMLQRDFGYRVYKMLLSLPEKVVSPPEPEKEEAAKEEATKEEEAIKEEVVKEPKD
  EAQNEGPATESEAPLKEDGLLPKPLSSGGEEEEKPRGEASEDLCEMALDPELLLLRDDGE
  EEFAGAKLEDSEVRSVASNQSEMEFSSLQDMPKELDPSAVLPLDCLLAFVFFDANWCGYL
  HRRDLERILLTLGIRLSAEQAKQLVSRVVTQNICQYRSLQYSRQEGLDGGLPEEVLFGNL
  DLLPPPGKSTKPGAAPTEHKALVSHNGSLINVGSLLQRAEQQDSGRLYLENKIHTLELKL
  EESHNRFSATEVTNKTLAAEMQELRVRLAEAEETARTAERQKSQLQRLLQELRRRLTPLQ
  LEIQRVVEKADSWVEKEEPAPSN
• Function: Core component of the DBIRD complex, a multiprotein complex that acts at the interface between core mRNP particles and RNA polymerase II (RNAPII) and integrates transcript elongation with the regulation of alternative splicing: the DBIRD complex affects local transcript elongation rates and alternative splicing of a large set of exons embedded in (A + T)-rich DNA regions. Inhibits SIRT1 deacetylase activity leading to increasing levels of p53/TP53 acetylation and p53-mediated apoptosis. Inhibits SUV39H1 methyltransferase activity. Mediates ligand-dependent transcriptional activation by nuclear hormone receptors. Plays a critical role in maintaining genomic stability and cellular integrity following UV-induced genotoxic stress. Regulates the circadian expression of the core clock components NR1D1 and BMAL1. Enhances the transcriptional repressor activity of NR1D1 through stabilization of NR1D1 protein levels by preventing its ubiquitination and subsequent degradation. Represses the ligand-dependent transcriptional activation function of ESR2. Acts as a regulator of PCK1 expression and gluconeogenesis by a mechanism that involves, at least in part, both NR1D1 and SIRT1. Negatively regulates the deacetylase activity of HDAC3 and can alter its subcellular localization. Positively regulates the beta-catenin pathway (canonical Wnt signaling pathway) and is required for MCC-mediated repression of the beta-catenin pathway. Represses ligand-dependent transcriptional activation function of NR1H2 and NR1H3 and inhibits the interaction of SIRT1 with NR1H3. Plays an important role in tumor suppression through p53/TP53 regulation; stabilizes p53/TP53 by affecting its interaction with ubiquitin ligase MDM2. Represses the transcriptional activator activity of BRCA1. Inhibits SIRT1 in a CHEK2 and PSEM3-dependent manner and inhibits the activity of CHEK2 in vitro.
• Tissue Specificity: Expressed in gastric carcinoma tissue and the expression gradually increases with the progression of the carcinoma (at protein level). Expressed ubiquitously in normal tissues. Expressed in 84 to 100% of neoplastic breast, lung, and colon tissues.
• KEGG Pathway: Wnt sig.ling pathway (hsa04310)
• Reactome Pathway: Regulation of HSF1-mediated heat shock response (R-HSA-3371453)

Molecular Interaction Atlas (MIA) of This DOT

38 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Lung adenocarcinoma	DISD51WR	Definitive	Genetic Variation	[1]
Lung squamous cell carcinoma	DISXPIBD	Definitive	Genetic Variation	[1]
Acute lymphocytic leukaemia	DISPX75S	Strong	Altered Expression	[2]
Aerodigestive tract cancer	DIS3AOQ7	Strong	Altered Expression	[3]
Arteriosclerosis	DISK5QGC	Strong	Genetic Variation	[4]
Atherosclerosis	DISMN9J3	Strong	Genetic Variation	[4]
Bladder cancer	DISUHNM0	Strong	Biomarker	[5]
Breast cancer	DIS7DPX1	Strong	Biomarker	[6]
Breast carcinoma	DIS2UE88	Strong	Biomarker	[6]
Breast neoplasm	DISNGJLM	Strong	Biomarker	[7]
Colorectal adenoma	DISTSVHM	Strong	Biomarker	[8]
Colorectal carcinoma	DIS5PYL0	Strong	Biomarker	[9]
Esophageal squamous cell carcinoma	DIS5N2GV	Strong	Altered Expression	[10]
Fatty liver disease	DIS485QZ	Strong	Biomarker	[11]
Malignant soft tissue neoplasm	DISTC6NO	Strong	Biomarker	[12]
Matthew-Wood syndrome	DISA7HR7	Strong	Altered Expression	[13]
Neoplasm	DISZKGEW	Strong	Biomarker	[14]
Neuroblastoma	DISVZBI4	Strong	Biomarker	[15]
Obesity	DIS47Y1K	Strong	Biomarker	[11]
Prostate cancer	DISF190Y	Strong	Biomarker	[16]
Prostate carcinoma	DISMJPLE	Strong	Biomarker	[16]
Sarcoma	DISZDG3U	Strong	Biomarker	[12]
Soft tissue sarcoma	DISSN8XB	Strong	Biomarker	[12]
Squamous cell carcinoma	DISQVIFL	Strong	Biomarker	[17]
Stomach cancer	DISKIJSX	Strong	Biomarker	[18]
Transitional cell carcinoma	DISWVVDR	Strong	Genetic Variation	[19]
Urinary bladder cancer	DISDV4T7	Strong	Biomarker	[5]
Urinary bladder neoplasm	DIS7HACE	Strong	Biomarker	[5]
Urothelial carcinoma	DISRTNTN	Strong	Genetic Variation	[19]
Carcinoma	DISH9F1N	moderate	Biomarker	[12]
Colon cancer	DISVC52G	moderate	Biomarker	[9]
Colon carcinoma	DISJYKUO	moderate	Biomarker	[9]
Hepatocellular carcinoma	DIS0J828	moderate	Altered Expression	[20]
Lung cancer	DISCM4YA	Disputed	Posttranslational Modification	[21]
Castration-resistant prostate carcinoma	DISVGAE6	Limited	Biomarker	[22]
Gastric cancer	DISXGOUK	Limited	Biomarker	[18]
Myasthenia gravis	DISELRCI	Limited	Biomarker	[23]
Non-insulin dependent diabetes	DISK1O5Z	Limited	Altered Expression	[24]

4 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 Cell cycle and apoptosis regulator protein 2 (CCAR2).	[25]
Doxorubicin	DMVP5YE	Approved	Doxorubicin decreases the expression of Cell cycle and apoptosis regulator protein 2 (CCAR2).	[26]
Ivermectin	DMDBX5F	Approved	Ivermectin decreases the expression of Cell cycle and apoptosis regulator protein 2 (CCAR2).	[27]
Menadione	DMSJDTY	Approved	Menadione affects the expression of Cell cycle and apoptosis regulator protein 2 (CCAR2).	[28]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene affects the methylation of Cell cycle and apoptosis regulator protein 2 (CCAR2).	[29]
TAK-243	DM4GKV2	Phase 1	TAK-243 increases the sumoylation of Cell cycle and apoptosis regulator protein 2 (CCAR2).	[30]
PMID28870136-Compound-52	DMFDERP	Patented	PMID28870136-Compound-52 increases the phosphorylation of Cell cycle and apoptosis regulator protein 2 (CCAR2).	[31]

References

• [1] Distinct HIC1-SIRT1-p53 loop deregulation in lung squamous carcinoma and adenocarcinoma patients.Neoplasia. 2009 Aug;11(8):763-70. doi: 10.1593/neo.09470.
• [2] Downregulation of DBC1 expression in acute lymphoblastic leukaemia is mediated by aberrant methylation of its promoter.Br J Haematol. 2006 Jul;134(2):137-44. doi: 10.1111/j.1365-2141.2006.06131.x.
• [3] Deleted in Breast Cancer 1 as a Novel Prognostic Biomarker for Digestive System Cancers: A Meta-Analysis.J Cancer. 2019 Mar 3;10(7):1633-1641. doi: 10.7150/jca.26935. eCollection 2019.
• [4] Deleted in breast cancer 1 limits adipose tissue fat accumulation and plays a key role in the development of metabolic syndrome phenotype.Diabetes. 2015 Jan;64(1):12-22. doi: 10.2337/db14-0192. Epub 2014 Jul 22.
• [5] Detection of bladder cancer using novel DNA methylation biomarkers in urine sediments.Cancer Epidemiol Biomarkers Prev. 2011 Jul;20(7):1483-91. doi: 10.1158/1055-9965.EPI-11-0067. Epub 2011 May 17.
• [6] The LIM protein Ajuba recruits DBC1 and CBP/p300 to acetylate ER and enhances ER target gene expression in breast cancer cells.Nucleic Acids Res. 2019 Mar 18;47(5):2322-2335. doi: 10.1093/nar/gky1306.
• [7] Negative regulation of the deacetylase SIRT1 by DBC1.Nature. 2008 Jan 31;451(7178):587-90. doi: 10.1038/nature06515.
• [8] The c-MYC/NAMPT/SIRT1 feedback loop is activated in early classical and serrated route colorectal cancer and represents a therapeutic target.Med Oncol. 2018 Nov 20;36(1):5. doi: 10.1007/s12032-018-1225-1.
• [9] DBC1 regulates Wnt/-catenin-mediated expression of MACC1, a key regulator of cancer progression, in colon cancer.Cell Death Dis. 2018 Aug 6;9(8):831. doi: 10.1038/s41419-018-0899-9.
• [10] The overexpression of DBC1 in esophageal squamous cell carcinoma correlates with poor prognosis.Histol Histopathol. 2012 Jan;27(1):49-58. doi: 10.14670/HH-27.49.
• [11] Deleted in breast cancer-1 regulates SIRT1 activity and contributes to high-fat diet-induced liver steatosis in mice.J Clin Invest. 2010 Feb;120(2):545-58. doi: 10.1172/JCI39319. Epub 2010 Jan 11.
• [12] Expression of SIRT1 and DBC1 is associated with poor prognosis of soft tissue sarcomas.PLoS One. 2013 Sep 3;8(9):e74738. doi: 10.1371/journal.pone.0074738. eCollection 2013.
• [13] Sirtuin-1 regulates acinar-to-ductal metaplasia and supports cancer cell viability in pancreatic cancer.Cancer Res. 2013 Apr 1;73(7):2357-67. doi: 10.1158/0008-5472.CAN-12-3359. Epub 2013 Jan 31.
• [14] Cell cycle and apoptosis regulator 2 at the interface between DNA damage response and cell physiology.Mutat Res Rev Mutat Res. 2018 Apr-Jun;776:1-9. doi: 10.1016/j.mrrev.2018.03.004. Epub 2018 Mar 19.
• [15] CCAR2/DBC1 and Hsp60 Positively Regulate Expression of Survivin in Neuroblastoma Cells.Int J Mol Sci. 2019 Jan 1;20(1):131. doi: 10.3390/ijms20010131.
• [16] Deleted in breast cancer 1, a novel androgen receptor (AR) coactivator that promotes AR DNA-binding activity.J Biol Chem. 2009 Mar 13;284(11):6832-40. doi: 10.1074/jbc.M808988200. Epub 2009 Jan 5.
• [17] CCAR2 Is Required for Proliferation and Tumor Maintenance in Human Squamous Cell Carcinoma.J Invest Dermatol. 2017 Feb;137(2):506-512. doi: 10.1016/j.jid.2016.09.027. Epub 2016 Oct 7.
• [18] NANOGP8 expression regulates gastric cancer cell progression by transactivating DBC1 in gastric cancer MKN-45 cells.Oncol Lett. 2019 Jan;17(1):555-563. doi: 10.3892/ol.2018.9595. Epub 2018 Oct 18.
• [19] Loss of heterozygosity at 9q32-33 (DBC1 locus) in primary non-invasive papillary urothelial neoplasm of low malignant potential and low-grade urothelial carcinoma of the bladder and their associated normal urothelium.J Pathol. 2008 Jul;215(3):263-72. doi: 10.1002/path.2353.
• [20] Overexpression of DBC1, correlated with poor prognosis, is a potential therapeutic target for hepatocellular carcinoma.Biochem Biophys Res Commun. 2017 Dec 16;494(3-4):511-517. doi: 10.1016/j.bbrc.2017.10.134. Epub 2017 Oct 26.
• [21] Frequent silencing of DBC1 is by genetic or epigenetic mechanisms in non-small cell lung cancers.Hum Mol Genet. 2005 Apr 15;14(8):997-1007. doi: 10.1093/hmg/ddi092. Epub 2005 Mar 3.
• [22] DBC1 promotes castration-resistant prostate cancer by positively regulating DNA binding and stability of AR-V7.Oncogene. 2018 Mar;37(10):1326-1339. doi: 10.1038/s41388-017-0047-5. Epub 2017 Dec 18.
• [23] DBC1 is a suppressor of B cell activation by negatively regulating alternative NF-B transcriptional activity.J Immunol. 2014 Dec 1;193(11):5515-24. doi: 10.4049/jimmunol.1401798. Epub 2014 Oct 31.
• [24] Augmentation of histone deacetylase 3 (HDAC3) epigenetic signature at the interface of proinflammation and insulin resistance in patients with type 2 diabetes.Clin Epigenetics. 2016 Nov 24;8:125. doi: 10.1186/s13148-016-0293-3. eCollection 2016.
• [25] Human embryonic stem cell-derived test systems for developmental neurotoxicity: a transcriptomics approach. Arch Toxicol. 2013 Jan;87(1):123-43.
• [26] 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.
• [27] 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.
• [28] 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.
• [29] 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.
• [30] 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.
• [31] Quantitative phosphoproteomics reveal cellular responses from caffeine, coumarin and quercetin in treated HepG2 cells. Toxicol Appl Pharmacol. 2022 Aug 15;449:116110. doi: 10.1016/j.taap.2022.116110. Epub 2022 Jun 7.