Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTN41QXP)

• DOT Name: Ribosomal oxygenase 1 (RIOX1)
• Synonyms: 60S ribosomal protein L8 histidine hydroxylase; Bifunctional lysine-specific demethylase and histidyl-hydroxylase NO66; EC 1.14.11.27, EC 1.14.11.79; Myc-associated protein with JmjC domain; Nucleolar protein 66; hsNO66; Ribosomal oxygenase NO66; ROX
• Gene Name: RIOX1
• Related Disease:
  Ankylosing spondylitis
  Spondyloarthropathy
  Adult glioblastoma
  Advanced cancer
  Breast cancer
  Breast carcinoma
  Breast neoplasm
  Castration-resistant prostate carcinoma
  Clear cell renal carcinoma
  Colorectal carcinoma
  Glioblastoma multiforme
  Glioma
  Lung cancer
  Lung carcinoma
  Medulloblastoma
  Neoplasm
  Prostate neoplasm
  Factor IX deficiency
  Subarachnoid hemorrhage
• UniProt ID: RIOX1_HUMAN
• PDB ID: 4CCJ; 4CCK; 4CCM; 4CCN; 4CCO; 4DIQ; 4E4H; 4Y33; 4Y3O; 4Y4R
• EC Number: 1.14.11.27; 1.14.11.79
• Pfam ID: PF08007 ; PF21233
• Sequence:
  MDGLQASAGPLRRGRPKRRRKPQPHSGSVLALPLRSRKIRKQLRSVVSRMAALRTQTLPS
  ENSEESRVESTADDLGDALPGGAAVAAVPDAARREPYGHLGPAELLEASPAARSLQTPSA
  RLVPASAPPARLVEVPAAPVRVVETSALLCTAQHLAAVQSSGAPATASGPQVDNTGGEPA
  WDSPLRRVLAELNRIPSSRRRAARLFEWLIAPMPPDHFYRRLWEREAVLVRRQDHTYYQG
  LFSTADLDSMLRNEEVQFGQHLDAARYINGRRETLNPPGRALPAAAWSLYQAGCSLRLLC
  PQAFSTTVWQFLAVLQEQFGSMAGSNVYLTPPNSQGFAPHYDDIEAFVLQLEGRKLWRVY
  RPRVPTEELALTSSPNFSQDDLGEPVLQTVLEPGDLLYFPRGFIHQAECQDGVHSLHLTL
  STYQRNTWGDFLEAILPLAVQAAMEENVEFRRGLPRDFMDYMGAQHSDSKDPRRTAFMEK
  VRVLVARLGHFAPVDAVADQRAKDFIHDSLPPVLTDRERALSVYGLPIRWEAGEPVNVGA
  QLTTETEVHMLQDGIARLVGEGGHLFLYYTVENSRVYHLEEPKCLEIYPQQADAMELLLG
  SYPEFVRVGDLPCDSVEDQLSLATTLYDKGLLLTKMPLALN
• Function: Oxygenase that can act as both a histone lysine demethylase and a ribosomal histidine hydroxylase. Specifically demethylates 'Lys-4' (H3K4me) and 'Lys-36' (H3K36me) of histone H3, thereby playing a central role in histone code. Preferentially demethylates trimethylated H3 'Lys-4' (H3K4me3) and monomethylated H3 'Lys-4' (H3K4me1) residues, while it has weaker activity for dimethylated H3 'Lys-36' (H3K36me2). Acts as a regulator of osteoblast differentiation via its interaction with SP7/OSX by demethylating H3K4me and H3K36me, thereby inhibiting SP7/OSX-mediated promoter activation. Also catalyzes demethylation of non-histone proteins, such as CGAS: demethylation of monomethylated CGAS promotes interaction between CGAS and PARP1, followed by PARP1 inactivation. Also catalyzes the hydroxylation of 60S ribosomal protein L8 on 'His-216', thereby playing a role in ribosome biogenesis. Participates in MYC-induced transcriptional activation.
• Tissue Specificity: Widely expressed. Overexpressed in lung carcinomas.
• Reactome Pathway: Protein hydroxylation (R-HSA-9629569)
• BioCyc Pathway: MetaCyc:ENSG00000170468-MONOMER

Molecular Interaction Atlas (MIA) of This DOT

19 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Ankylosing spondylitis	DISRC6IR	Definitive	Biomarker	[1]
Spondyloarthropathy	DISBPYCZ	Definitive	Biomarker	[1]
Adult glioblastoma	DISVP4LU	Strong	Altered Expression	[2]
Advanced cancer	DISAT1Z9	Strong	Biomarker	[3]
Breast cancer	DIS7DPX1	Strong	Genetic Variation	[4]
Breast carcinoma	DIS2UE88	Strong	Genetic Variation	[4]
Breast neoplasm	DISNGJLM	Strong	Genetic Variation	[4]
Castration-resistant prostate carcinoma	DISVGAE6	Strong	Biomarker	[5]
Clear cell renal carcinoma	DISBXRFJ	Strong	Posttranslational Modification	[6]
Colorectal carcinoma	DIS5PYL0	Strong	Altered Expression	[3]
Glioblastoma multiforme	DISK8246	Strong	Altered Expression	[2]
Glioma	DIS5RPEH	Strong	Altered Expression	[2]
Lung cancer	DISCM4YA	Strong	Altered Expression	[7]
Lung carcinoma	DISTR26C	Strong	Altered Expression	[7]
Medulloblastoma	DISZD2ZL	Strong	Biomarker	[8]
Neoplasm	DISZKGEW	Strong	Altered Expression	[5]
Prostate neoplasm	DISHDKGQ	Strong	Altered Expression	[5]
Factor IX deficiency	DISHN9SC	moderate	Biomarker	[9]
Subarachnoid hemorrhage	DISI7I8Y	Limited	Biomarker	[10]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Doxorubicin	DMVP5YE	Approved	Doxorubicin decreases the expression of Ribosomal oxygenase 1 (RIOX1).	[11]
Cupric Sulfate	DMP0NFQ	Approved	Cupric Sulfate decreases the expression of Ribosomal oxygenase 1 (RIOX1).	[12]
Estradiol	DMUNTE3	Approved	Estradiol increases the expression of Ribosomal oxygenase 1 (RIOX1).	[13]
Temozolomide	DMKECZD	Approved	Temozolomide decreases the expression of Ribosomal oxygenase 1 (RIOX1).	[14]
Hydrogen peroxide	DM1NG5W	Approved	Hydrogen peroxide affects the expression of Ribosomal oxygenase 1 (RIOX1).	[15]
THAPSIGARGIN	DMDMQIE	Preclinical	THAPSIGARGIN decreases the expression of Ribosomal oxygenase 1 (RIOX1).	[17]
Formaldehyde	DM7Q6M0	Investigative	Formaldehyde decreases the expression of Ribosomal oxygenase 1 (RIOX1).	[18]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
PMID28870136-Compound-52	DMFDERP	Patented	PMID28870136-Compound-52 decreases the phosphorylation of Ribosomal oxygenase 1 (RIOX1).	[16]

References

• [1] Identification of pathways significantly associated with spondyloarthropathy/ankylosing spondylitis using the subpathway method.Mol Med Rep. 2018 Oct;18(4):3825-3833. doi: 10.3892/mmr.2018.9395. Epub 2018 Aug 17.
• [2] The Histone Demethylase NO66 Induces Glioma Cell Proliferation.Anticancer Res. 2019 Nov;39(11):6007-6014. doi: 10.21873/anticanres.13806.
• [3] Clinical Significance of Histone Demethylase NO66 in Invasive Colorectal Cancer.Ann Surg Oncol. 2017 Mar;24(3):841-849. doi: 10.1245/s10434-016-5395-9. Epub 2016 Jul 29.
• [4] The human ROX gene: genomic structure and mutation analysis in human breast tumors.Genomics. 1998 Apr 15;49(2):275-82. doi: 10.1006/geno.1998.5241.
• [5] Oncogenic and osteolytic functions of histone demethylase NO66 in castration-resistant prostate cancer.Oncogene. 2019 Jun;38(25):5038-5049. doi: 10.1038/s41388-019-0774-x. Epub 2019 Mar 11.
• [6] SETDB2 and RIOX2 are differentially expressed among renal cell tumor subtypes, associating with prognosis and metastization.Epigenetics. 2017;12(12):1057-1064. doi: 10.1080/15592294.2017.1385685. Epub 2018 Jan 22.
• [7] Identification of Myc-associated protein with JmjC domain as a novel therapeutic target oncogene for lung cancer.Mol Cancer Ther. 2007 Feb;6(2):542-51. doi: 10.1158/1535-7163.MCT-06-0659.
• [8] Analysis of transcripts from 17p13.3 in medulloblastoma suggests ROX/MNT as a potential tumour suppressor gene.Eur J Cancer. 2004 Nov;40(16):2525-32. doi: 10.1016/j.ejca.2004.08.005.
• [9] Qualification of a select one-stage activated partial thromboplastin time-based clotting assay and two chromogenic assays for the post-administration monitoring of nonacog beta pegol.J Thromb Haemost. 2017 Oct;15(10):1901-1912. doi: 10.1111/jth.13787. Epub 2017 Sep 11.
• [10] A novel fluorescent imaging technique for assessment of cerebral vasospasm after experimental subarachnoid hemorrhage.Sci Rep. 2017 Aug 22;7(1):9126. doi: 10.1038/s41598-017-09070-y.
• [11] 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.
• [12] Physiological and toxicological transcriptome changes in HepG2 cells exposed to copper. Physiol Genomics. 2009 Aug 7;38(3):386-401.
• [13] 17-Estradiol Activates HSF1 via MAPK Signaling in ER-Positive Breast Cancer Cells. Cancers (Basel). 2019 Oct 11;11(10):1533. doi: 10.3390/cancers11101533.
• [14] 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.
• [15] 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.
• [16] 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.
• [17] Endoplasmic reticulum stress impairs insulin signaling through mitochondrial damage in SH-SY5Y cells. Neurosignals. 2012;20(4):265-80.
• [18] Gene expression changes in primary human nasal epithelial cells exposed to formaldehyde in vitro. Toxicol Lett. 2010 Oct 5;198(2):289-95.