Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTE76DY5)

• DOT Name: RWD domain-containing protein 3 (RWDD3)
• Synonyms: RWD domain-containing sumoylation enhancer; RSUME
• Gene Name: RWDD3
• Related Disease:
  Glioma
  Hemangioblastoma
  Neoplasm
  Pheochromocytoma
  Von hippel-lindau disease
  Clear cell renal carcinoma
  Adult glioblastoma
  Glioblastoma multiforme
  Renal cell carcinoma
• UniProt ID: RWDD3_HUMAN
• PDB ID: 2EBK; 4Y1L
• Pfam ID: PF05773
• Sequence:
  MAEPVQEELSVLAAIFCRPHEWEVLSRSETDGTVFRIHTKAEGFMDVDIPLELVFHLPVN
  YPSCLPGISINSEQLTRAQCVTVKENLLEQAESLLSEPMVHELVLWIQQNLRHILSQPET
  GSGSEKCTFSTSTTMDDGLWITLLHLDHMRAKTKYVKIVEKWASDLRLTGRLMFMGKIIL
  ILLQGDRNNLKEYLILQKTSKVDVDSSGKKCKEKMISVLFETKVQTEHKRFLAFEVKEYS
  ALDELQKEFETAGLKKLFSEFVLALVK
• Function: Enhancer of SUMO conjugation. Via its interaction with UBE2I/UBC9, increases SUMO conjugation to proteins by promoting the binding of E1 and E2 enzymes, thioester linkage between SUMO and UBE2I/UBC9 and transfer of SUMO to specific target proteins which include HIF1A, PIAS, NFKBIA, NR3C1 and TOP1. Isoform 1 and isoform 2 positively regulate the NF-kappa-B signaling pathway by enhancing the sumoylation of NF-kappa-B inhibitor alpha (NFKBIA), promoting its stabilization which consequently leads to an increased inhibition of NF-kappa-B transcriptional activity. Isoform 1 and isoform 2 negatively regulate the hypoxia-inducible factor-1 alpha (HIF1A) signaling pathway by increasing the sumoylation of HIF1A, promoting its stabilization, transcriptional activity and the expression of its target gene VEGFA during hypoxia. Isoform 2 promotes the sumoylation and transcriptional activity of the glucocorticoid receptor NR3C1 and enhances the interaction of SUMO1 and NR3C1 with UBE2I/UBC9. Has no effect on ubiquitination.
• Tissue Specificity: Isoform 1 and isoform 2 are expressed in glioma tumors (at protein level). Expressed in a wide number of tissues with highest expression in cerebellum, pituitary, heart, kidney, liver, stomach, pancreas, prostate and spleen. Low levels in thalamus, spinal cord, esophagus, thymus, lung and peripheral blood leukocytes. A higher level expression seen in pituitary tumors as compared to the pituitary gland.
• Reactome Pathway: SUMO is transferred from E1 to E2 (UBE2I, UBC9) (R-HSA-3065678)

Molecular Interaction Atlas (MIA) of This DOT

9 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Glioma	DIS5RPEH	Strong	Altered Expression	[1]
Hemangioblastoma	DIS1EAZC	Strong	Biomarker	[2]
Neoplasm	DISZKGEW	Strong	Biomarker	[3]
Pheochromocytoma	DIS56IFV	Strong	Biomarker	[2]
Von hippel-lindau disease	DIS6ZFQQ	Strong	Altered Expression	[2]
Clear cell renal carcinoma	DISBXRFJ	moderate	Altered Expression	[3]
Adult glioblastoma	DISVP4LU	Limited	Altered Expression	[4]
Glioblastoma multiforme	DISK8246	Limited	Altered Expression	[4]
Renal cell carcinoma	DISQZ2X8	Limited	Altered Expression	[3]

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 RWD domain-containing protein 3 (RWDD3).	[5]
Ciclosporin	DMAZJFX	Approved	Ciclosporin decreases the expression of RWD domain-containing protein 3 (RWDD3).	[6]
Cupric Sulfate	DMP0NFQ	Approved	Cupric Sulfate decreases the expression of RWD domain-containing protein 3 (RWDD3).	[7]
Estradiol	DMUNTE3	Approved	Estradiol decreases the expression of RWD domain-containing protein 3 (RWDD3).	[8]
Vorinostat	DMWMPD4	Approved	Vorinostat decreases the expression of RWD domain-containing protein 3 (RWDD3).	[9]
Methotrexate	DM2TEOL	Approved	Methotrexate increases the expression of RWD domain-containing protein 3 (RWDD3).	[9]
Niclosamide	DMJAGXQ	Approved	Niclosamide decreases the expression of RWD domain-containing protein 3 (RWDD3).	[10]
Camptothecin	DM6CHNJ	Phase 3	Camptothecin increases the expression of RWD domain-containing protein 3 (RWDD3).	[9]
Pracinostat	DMTD7AB	Phase 3	Pracinostat decreases the expression of RWD domain-containing protein 3 (RWDD3).	[9]
PMID28460551-Compound-2	DM4DOUB	Patented	PMID28460551-Compound-2 decreases the expression of RWD domain-containing protein 3 (RWDD3).	[12]
Scriptaid	DM9JZ21	Preclinical	Scriptaid decreases the expression of RWD domain-containing protein 3 (RWDD3).	[9]
Trichostatin A	DM9C8NX	Investigative	Trichostatin A affects the expression of RWD domain-containing protein 3 (RWDD3).	[13]
methyl p-hydroxybenzoate	DMO58UW	Investigative	methyl p-hydroxybenzoate decreases the expression of RWD domain-containing protein 3 (RWDD3).	[14]
Octanedioic acid bis-hydroxyamide	DMJNQ9K	Investigative	Octanedioic acid bis-hydroxyamide decreases the expression of RWD domain-containing protein 3 (RWDD3).	[9]

1 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 RWD domain-containing protein 3 (RWDD3).	[11]

References

• [1] MicroRNA-375 inhibits glioma cell proliferation and migration by downregulating RWDD3 invitro.Oncol Rep. 2018 Apr;39(4):1825-1834. doi: 10.3892/or.2018.6261. Epub 2018 Feb 13.
• [2] RSUME inhibits VHL and regulates its tumor suppressor function.Oncogene. 2015 Sep 10;34(37):4855-66. doi: 10.1038/onc.2014.407. Epub 2014 Dec 15.
• [3] von Hippel-Lindau mutants in renal cell carcinoma are regulated by increased expression of RSUME.Cell Death Dis. 2019 Mar 19;10(4):266. doi: 10.1038/s41419-019-1507-3.
• [4] Knockdown of RWD domain containing 3 inhibits the malignant phenotypes of glioblastoma cells via inhibition of phosphoinositide 3-kinase/protein kinase B signaling.Exp Ther Med. 2018 Jul;16(1):384-393. doi: 10.3892/etm.2018.6135. Epub 2018 May 7.
• [5] Human embryonic stem cell-derived test systems for developmental neurotoxicity: a transcriptomics approach. Arch Toxicol. 2013 Jan;87(1):123-43.
• [6] 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.
• [7] Physiological and toxicological transcriptome changes in HepG2 cells exposed to copper. Physiol Genomics. 2009 Aug 7;38(3):386-401.
• [8] 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.
• [9] Development and validation of the TGx-HDACi transcriptomic biomarker to detect histone deacetylase inhibitors in human TK6 cells. Arch Toxicol. 2021 May;95(5):1631-1645. doi: 10.1007/s00204-021-03014-2. Epub 2021 Mar 26.
• [10] Mitochondrial Uncoupling Induces Epigenome Remodeling and Promotes Differentiation in Neuroblastoma. Cancer Res. 2023 Jan 18;83(2):181-194. doi: 10.1158/0008-5472.CAN-22-1029.
• [11] 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.
• [12] Cell-based two-dimensional morphological assessment system to predict cancer drug-induced cardiotoxicity using human induced pluripotent stem cell-derived cardiomyocytes. Toxicol Appl Pharmacol. 2019 Nov 15;383:114761. doi: 10.1016/j.taap.2019.114761. Epub 2019 Sep 15.
• [13] 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.
• [14] Transcriptome dynamics of alternative splicing events revealed early phase of apoptosis induced by methylparaben in H1299 human lung carcinoma cells. Arch Toxicol. 2020 Jan;94(1):127-140. doi: 10.1007/s00204-019-02629-w. Epub 2019 Nov 20.