Details of Drug Off-Target (DOT)

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

• DOT Name: Protein RCC2 (RCC2)
• Synonyms: RCC1-like protein TD-60; Telophase disk protein of 60 kDa
• Gene Name: RCC2
• Related Disease:
  Advanced cancer
  Breast cancer
  Breast carcinoma
  Epithelial ovarian cancer
  Lung adenocarcinoma
  Lung cancer
  Lung carcinoma
  Neoplasm
  Ovarian cancer
  Ovarian neoplasm
  Colorectal carcinoma
  Metastatic malignant neoplasm
  Adult glioblastoma
  Basal cell carcinoma
  Basal cell neoplasm
  Glioblastoma multiforme
  Marinesco-Sjogren syndrome
  Rectal carcinoma
• UniProt ID: RCC2_HUMAN
• PDB ID: 5GWN
• Pfam ID: PF00415
• Sequence:
  MPRKKAAAAAWEEPSSGNGTARAGPRKRGGPAGRKRERPERCSSSSGGGSSGDEDGLELD
  GAPGGGKRAARPATAGKAGGAAVVITEPEHTKERVKLEGSKCKGQLLIFGATNWDLIGRK
  EVPKQQAAYRNLGQNLWGPHRYGCLAGVRVRTVVSGSCAAHSLLITTEGKLWSWGRNEKG
  QLGHGDTKRVEAPRLIEGLSHEVIVSAACGRNHTLALTETGSVFAFGENKMGQLGLGNQT
  DAVPSPAQIMYNGQPITKMACGAEFSMIMDCKGNLYSFGCPEYGQLGHNSDGKFIARAQR
  IEYDCELVPRRVAIFIEKTKDGQILPVPNVVVRDVACGANHTLVLDSQKRVFSWGFGGYG
  RLGHAEQKDEMVPRLVKLFDFPGRGASQIYAGYTCSFAVSEVGGLFFWGATNTSRESTMY
  PKAVQDLCGWRIRSLACGKSSIIVAADESTISWGPSPTFGELGYGDHKPKSSTAAQEVKT
  LDGIFSEQVAMGYSHSLVIARDESETEKEKIKKLPEYNPRTL
• Function: Multifunctional protein that may affect its functions by regulating the activity of small GTPases, such as RAC1 and RALA. Required for normal progress through the cell cycle, both during interphase and during mitosis. Required for the presence of normal levels of MAD2L1, AURKB and BIRC5 on inner centromeres during mitosis, and for normal attachment of kinetochores to mitotic spindles. Required for normal organization of the microtubule cytoskeleton in interphase cells. Functions as guanine nucleotide exchange factor (GEF) for RALA. Interferes with the activation of RAC1 by guanine nucleotide exchange factors. Prevents accumulation of active, GTP-bound RAC1, and suppresses RAC1-mediated reorganization of the actin cytoskeleton and formation of membrane protrusions. Required for normal cellular responses to contacts with the extracellular matrix of adjacent cells, and for directional cell migration in response to a fibronectin gradient (in vitro).
• Reactome Pathway:
  Separation of Sister Chromatids (R-HSA-2467813)
  Resolution of Sister Chromatid Cohesion (R-HSA-2500257)
  RHO GTPases Activate Formins (R-HSA-5663220)
  Mitotic Prometaphase (R-HSA-68877)
  EML4 and NUDC in mitotic spindle formation (R-HSA-9648025)
  Amplification of signal from unattached kinetochores via a MAD2 inhibitory signal (R-HSA-141444)

Molecular Interaction Atlas (MIA) of This DOT

18 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Advanced cancer	DISAT1Z9	Strong	Biomarker	[1]
Breast cancer	DIS7DPX1	Strong	Biomarker	[2]
Breast carcinoma	DIS2UE88	Strong	Biomarker	[2]
Epithelial ovarian cancer	DIS56MH2	Strong	Biomarker	[3]
Lung adenocarcinoma	DISD51WR	Strong	Biomarker	[4]
Lung cancer	DISCM4YA	Strong	Altered Expression	[5]
Lung carcinoma	DISTR26C	Strong	Altered Expression	[5]
Neoplasm	DISZKGEW	Strong	Biomarker	[6]
Ovarian cancer	DISZJHAP	Strong	Biomarker	[3]
Ovarian neoplasm	DISEAFTY	Strong	Biomarker	[3]
Colorectal carcinoma	DIS5PYL0	moderate	Biomarker	[1]
Metastatic malignant neoplasm	DIS86UK6	moderate	Biomarker	[6]
Adult glioblastoma	DISVP4LU	Limited	Biomarker	[6]
Basal cell carcinoma	DIS7PYN3	Limited	Genetic Variation	[7]
Basal cell neoplasm	DIS37IXW	Limited	Genetic Variation	[7]
Glioblastoma multiforme	DISK8246	Limited	Biomarker	[6]
Marinesco-Sjogren syndrome	DISKEU0B	Limited	Genetic Variation	[8]
Rectal carcinoma	DIS8FRR7	Limited	Altered Expression	[8]

10 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 Protein RCC2 (RCC2).	[9]
Ciclosporin	DMAZJFX	Approved	Ciclosporin increases the expression of Protein RCC2 (RCC2).	[10]
Tretinoin	DM49DUI	Approved	Tretinoin decreases the expression of Protein RCC2 (RCC2).	[11]
Cisplatin	DMRHGI9	Approved	Cisplatin decreases the expression of Protein RCC2 (RCC2).	[12]
Ivermectin	DMDBX5F	Approved	Ivermectin decreases the expression of Protein RCC2 (RCC2).	[13]
Temozolomide	DMKECZD	Approved	Temozolomide increases the expression of Protein RCC2 (RCC2).	[15]
Belinostat	DM6OC53	Phase 2	Belinostat decreases the expression of Protein RCC2 (RCC2).	[16]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A decreases the expression of Protein RCC2 (RCC2).	[19]
Trichostatin A	DM9C8NX	Investigative	Trichostatin A decreases the expression of Protein RCC2 (RCC2).	[16]
Milchsaure	DM462BT	Investigative	Milchsaure decreases the expression of Protein RCC2 (RCC2).	[20]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Arsenic	DMTL2Y1	Approved	Arsenic affects the methylation of Protein RCC2 (RCC2).	[14]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene decreases the methylation of Protein RCC2 (RCC2).	[17]
TAK-243	DM4GKV2	Phase 1	TAK-243 increases the sumoylation of Protein RCC2 (RCC2).	[18]

References

• [1] RCC2 is a novel p53 target in suppressing metastasis.Oncogene. 2018 Jan 4;37(1):8-17. doi: 10.1038/onc.2017.306. Epub 2017 Sep 4.
• [2] RCC2 promotes breast cancer progression through regulation of Wnt signaling and inducing EMT.J Cancer. 2019 Nov 1;10(27):6837-6847. doi: 10.7150/jca.36430. eCollection 2019.
• [3] RCC2, a regulator of the RalA signaling pathway, is identified as a novel therapeutic target in cisplatin-resistant ovarian cancer.FASEB J. 2019 Apr;33(4):5350-5365. doi: 10.1096/fj.201801529RR. Epub 2019 Feb 15.
• [4] Overexpression of RCC2 Enhances Cell Motility and Promotes Tumor Metastasis in Lung Adenocarcinoma by Inducing Epithelial-Mesenchymal Transition.Clin Cancer Res. 2017 Sep 15;23(18):5598-5610. doi: 10.1158/1078-0432.CCR-16-2909. Epub 2017 Jun 12.
• [5] RCC2 over-expression in tumor cells alters apoptosis and drug sensitivity by regulating Rac1 activation.BMC Cancer. 2018 Jan 10;18(1):67. doi: 10.1186/s12885-017-3908-y.
• [6] RCC2 promotes proliferation and radio-resistance in glioblastoma via activating transcription of DNMT1.Biochem Biophys Res Commun. 2019 Aug 27;516(3):999-1006. doi: 10.1016/j.bbrc.2019.06.097. Epub 2019 Jul 2.
• [7] Combined analysis of keratinocyte cancers identifies novel genome-wide loci.Hum Mol Genet. 2019 Sep 15;28(18):3148-3160. doi: 10.1093/hmg/ddz121.
• [8] Regulator of Chromosome Condensation 2 Identifies High-Risk Patients within Both Major Phenotypes of Colorectal Cancer.Clin Cancer Res. 2015 Aug 15;21(16):3759-70. doi: 10.1158/1078-0432.CCR-14-3294. Epub 2015 Apr 24.
• [9] The neuroprotective action of the mood stabilizing drugs lithium chloride and sodium valproate is mediated through the up-regulation of the homeodomain protein Six1. Toxicol Appl Pharmacol. 2009 Feb 15;235(1):124-34.
• [10] Comparison of HepG2 and HepaRG by whole-genome gene expression analysis for the purpose of chemical hazard identification. Toxicol Sci. 2010 May;115(1):66-79.
• [11] Transcriptional and Metabolic Dissection of ATRA-Induced Granulocytic Differentiation in NB4 Acute Promyelocytic Leukemia Cells. Cells. 2020 Nov 5;9(11):2423. doi: 10.3390/cells9112423.
• [12] 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.
• [13] 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.
• [14] Prenatal arsenic exposure and the epigenome: identifying sites of 5-methylcytosine alterations that predict functional changes in gene expression in newborn cord blood and subsequent birth outcomes. Toxicol Sci. 2015 Jan;143(1):97-106. doi: 10.1093/toxsci/kfu210. Epub 2014 Oct 10.
• [15] 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.
• [16] Gene expression-signature of belinostat in cell lines is specific for histone deacetylase inhibitor treatment, with a corresponding signature in xenografts. Anticancer Drugs. 2009 Sep;20(8):682-92.
• [17] 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.
• [18] 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.
• [19] Low-dose Bisphenol A exposure alters the functionality and cellular environment in a human cardiomyocyte model. Environ Pollut. 2023 Oct 15;335:122359. doi: 10.1016/j.envpol.2023.122359. Epub 2023 Aug 9.
• [20] Transcriptional profiling of lactic acid treated reconstructed human epidermis reveals pathways underlying stinging and itch. Toxicol In Vitro. 2019 Jun;57:164-173.