Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OT60N06L)

• DOT Name: RCC1 domain-containing protein 1 (RCCD1)
• Gene Name: RCCD1
• Related Disease:
  Advanced cancer
  Breast cancer
  Breast carcinoma
  Breast neoplasm
  Epithelial ovarian cancer
  Lung adenocarcinoma
  Lung cancer
  Lung carcinoma
  Non-small-cell lung cancer
  Ovarian cancer
  Ovarian neoplasm
  Prostate cancer
  Prostate carcinoma
• UniProt ID: RCCD1_HUMAN
• PDB ID: 6F4R; 6F4S; 6F4T
• Pfam ID: PF00415
• Sequence:
  MAEERPGAWFGFGFCGFGQELGSGRGRQVHSPSPLRAGVDICRVSASWSYTAFVTRGGRL
  ELSGSASGAAGRCKDAWASEGLLAVLRAGPGPEALLQVWAAESALRGEPLWAQNVVPEAE
  GEDDPAGEAQAGRLPLLPCARAYVSPRAPFYRPLAPELRARQLELGAEHALLLDAAGQVF
  SWGGGRHGQLGHGTLEAELEPRLLEALQGLVMAEVAAGGWHSVCVSETGDIYIWGWNESG
  QLALPTRNLAEDGETVAREATELNEDGSQVKRTGGAEDGAPAPFIAVQPFPALLDLPMGS
  DAVKASCGSRHTAVVTRTGELYTWGWGKYGQLGHEDTTSLDRPRRVEYFVDKQLQVKAVT
  CGPWNTYVYAVEKGKS
• Function: Plays a role in transcriptional repression of satellite repeats, possibly by regulating H3K36 methylation levels in centromeric regions together with KDM8. Possibly together with KDM8, is involved in proper mitotic spindle organization and chromosome segregation. Plays a role in regulating alpha-tubulin deacetylation and cytoskeletal microtubule stability, thereby promoting cell migration and TGF-beta-induced epithelial to mesenchymal transition (EMT), potentially through the inhibition of KDM8.
• Reactome Pathway: Protein hydroxylation (R-HSA-9629569)

Molecular Interaction Atlas (MIA) of This DOT

13 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Advanced cancer	DISAT1Z9	Strong	Genetic Variation	[1]
Breast cancer	DIS7DPX1	Strong	Biomarker	[2]
Breast carcinoma	DIS2UE88	Strong	Biomarker	[2]
Breast neoplasm	DISNGJLM	Strong	Biomarker	[2]
Epithelial ovarian cancer	DIS56MH2	Strong	Genetic Variation	[1]
Lung adenocarcinoma	DISD51WR	Strong	Altered Expression	[3]
Lung cancer	DISCM4YA	Strong	Biomarker	[4]
Lung carcinoma	DISTR26C	Strong	Biomarker	[4]
Non-small-cell lung cancer	DIS5Y6R9	Strong	Biomarker	[4]
Ovarian cancer	DISZJHAP	Strong	Genetic Variation	[1]
Ovarian neoplasm	DISEAFTY	Strong	Genetic Variation	[1]
Prostate cancer	DISF190Y	Strong	Genetic Variation	[1]
Prostate carcinoma	DISMJPLE	Strong	Genetic Variation	[1]

14 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 RCC1 domain-containing protein 1 (RCCD1).	[5]
Ciclosporin	DMAZJFX	Approved	Ciclosporin decreases the expression of RCC1 domain-containing protein 1 (RCCD1).	[6]
Acetaminophen	DMUIE76	Approved	Acetaminophen increases the expression of RCC1 domain-containing protein 1 (RCCD1).	[7]
Doxorubicin	DMVP5YE	Approved	Doxorubicin decreases the expression of RCC1 domain-containing protein 1 (RCCD1).	[8]
Cupric Sulfate	DMP0NFQ	Approved	Cupric Sulfate decreases the expression of RCC1 domain-containing protein 1 (RCCD1).	[9]
Cisplatin	DMRHGI9	Approved	Cisplatin increases the expression of RCC1 domain-containing protein 1 (RCCD1).	[10]
Calcitriol	DM8ZVJ7	Approved	Calcitriol decreases the expression of RCC1 domain-containing protein 1 (RCCD1).	[12]
Testosterone	DM7HUNW	Approved	Testosterone decreases the expression of RCC1 domain-containing protein 1 (RCCD1).	[12]
Decitabine	DMQL8XJ	Approved	Decitabine affects the expression of RCC1 domain-containing protein 1 (RCCD1).	[13]
Sodium lauryl sulfate	DMLJ634	Approved	Sodium lauryl sulfate decreases the expression of RCC1 domain-containing protein 1 (RCCD1).	[14]
Urethane	DM7NSI0	Phase 4	Urethane decreases the expression of RCC1 domain-containing protein 1 (RCCD1).	[15]
Leflunomide	DMR8ONJ	Phase 1 Trial	Leflunomide decreases the expression of RCC1 domain-containing protein 1 (RCCD1).	[17]
Trichostatin A	DM9C8NX	Investigative	Trichostatin A affects the expression of RCC1 domain-containing protein 1 (RCCD1).	[18]
Coumestrol	DM40TBU	Investigative	Coumestrol increases the expression of RCC1 domain-containing protein 1 (RCCD1).	[19]

2 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 RCC1 domain-containing protein 1 (RCCD1).	[11]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene increases the methylation of RCC1 domain-containing protein 1 (RCCD1).	[16]

References

• [1] Genome-Wide Meta-Analyses of Breast, Ovarian, and Prostate Cancer Association Studies Identify Multiple New Susceptibility Loci Shared by at Least Two Cancer Types.Cancer Discov. 2016 Sep;6(9):1052-67. doi: 10.1158/2159-8290.CD-15-1227. Epub 2016 Jul 17.
• [2] A transcriptome-wide association study of 229,000 women identifies new candidate susceptibility genes for breast cancer.Nat Genet. 2018 Jul;50(7):968-978. doi: 10.1038/s41588-018-0132-x. Epub 2018 Jun 18.
• [3] LINC01419 promotes cell proliferation and metastasis in lung adenocarcinoma via sponging miR-519b-3p to up-regulate RCCD1.Biochem Biophys Res Commun. 2019 Nov 26;520(1):107-114. doi: 10.1016/j.bbrc.2019.09.090. Epub 2019 Sep 30.
• [4] RCCD1 depletion attenuates TGF--induced EMT and cell migration bystabilizing cytoskeletal microtubules in NSCLC cells.Cancer Lett. 2017 Aug 1;400:18-29. doi: 10.1016/j.canlet.2017.04.021. Epub 2017 Apr 26.
• [5] 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.
• [6] Integrating multiple omics to unravel mechanisms of Cyclosporin A induced hepatotoxicity in vitro. Toxicol In Vitro. 2015 Apr;29(3):489-501.
• [7] Predictive toxicology using systemic biology and liver microfluidic "on chip" approaches: application to acetaminophen injury. Toxicol Appl Pharmacol. 2012 Mar 15;259(3):270-80.
• [8] 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.
• [9] Physiological and toxicological transcriptome changes in HepG2 cells exposed to copper. Physiol Genomics. 2009 Aug 7;38(3):386-401.
• [10] Activation of AIFM2 enhances apoptosis of human lung cancer cells undergoing toxicological stress. Toxicol Lett. 2016 Sep 6;258:227-236.
• [11] 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.
• [12] Effects of 1alpha,25 dihydroxyvitamin D3 and testosterone on miRNA and mRNA expression in LNCaP cells. Mol Cancer. 2011 May 18;10:58.
• [13] Acute hypersensitivity of pluripotent testicular cancer-derived embryonal carcinoma to low-dose 5-aza deoxycytidine is associated with global DNA Damage-associated p53 activation, anti-pluripotency and DNA demethylation. PLoS One. 2012;7(12):e53003. doi: 10.1371/journal.pone.0053003. Epub 2012 Dec 27.
• [14] CXCL14 downregulation in human keratinocytes is a potential biomarker for a novel in vitro skin sensitization test. Toxicol Appl Pharmacol. 2020 Jan 1;386:114828. doi: 10.1016/j.taap.2019.114828. Epub 2019 Nov 14.
• [15] Ethyl carbamate induces cell death through its effects on multiple metabolic pathways. Chem Biol Interact. 2017 Nov 1;277:21-32.
• [16] 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.
• [17] Endoplasmic reticulum stress and MAPK signaling pathway activation underlie leflunomide-induced toxicity in HepG2 Cells. Toxicology. 2017 Dec 1;392:11-21.
• [18] A trichostatin A expression signature identified by TempO-Seq targeted whole transcriptome profiling. PLoS One. 2017 May 25;12(5):e0178302. doi: 10.1371/journal.pone.0178302. eCollection 2017.
• [19] Pleiotropic combinatorial transcriptomes of human breast cancer cells exposed to mixtures of dietary phytoestrogens. Food Chem Toxicol. 2009 Apr;47(4):787-95.