Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTAE7504)

• DOT Name: RING finger and CHY zinc finger domain-containing protein 1 (RCHY1)
• Synonyms: EC 2.3.2.27; Androgen receptor N-terminal-interacting protein; CH-rich-interacting match with PLAG1; E3 ubiquitin-protein ligase Pirh2; RING finger protein 199; RING-type E3 ubiquitin transferase RCHY1; Zinc finger protein 363; p53-induced RING-H2 protein; hPirh2
• Gene Name: RCHY1
• Related Disease:
  Adenocarcinoma
  Breast carcinoma
  Carcinoma
  Head-neck squamous cell carcinoma
  Hepatocellular carcinoma
  Kidney cancer
  Lung cancer
  Lung neoplasm
  Neoplasm
  Prostate cancer
  Prostate carcinoma
  Prostate neoplasm
  Renal carcinoma
  Rheumatoid arthritis
  Sciatic neuropathy
  Squamous cell carcinoma
  Breast cancer
  Colon cancer
  Colon carcinoma
  Plasma cell myeloma
• UniProt ID: ZN363_HUMAN
• PDB ID: 2JRJ; 2K2C; 2K2D; 7YNX
• EC Number: 2.3.2.27
• Pfam ID: PF05495 ; PF13639 ; PF14599
• Sequence:
  MAATAREDGASGQERGQRGCEHYDRGCLLKAPCCDKLYTCRLCHDNNEDHQLDRFKVKEV
  QCINCEKIQHAQQTCEECSTLFGEYYCDICHLFDKDKKQYHCENCGICRIGPKEDFFHCL
  KCNLCLAMNLQGRHKCIENVSRQNCPICLEDIHTSRVVAHVLPCGHLLHRTCYEEMLKEG
  YRCPLCMHSALDMTRYWRQLDDEVAQTPMPSEYQNMTVDILCNDCNGRSTVQFHILGMKC
  KICESYNTAQAGGRRISLDQQ
• Function: E3 ubiquitin-protein ligase that mediates ubiquitination of target proteins, including p53/TP53, TP73, HDAC1 and CDKN1B. Mediates ubiquitination and degradation of p53/TP53; preferentially acts on tetrameric p53/TP53. Catalyzes monoubiquitinates the translesion DNA polymerase POLH. Involved in the ribosome-associated quality control (RQC) pathway, which mediates the extraction of incompletely synthesized nascent chains from stalled ribosomes: RCHY1 acts downstream of NEMF and recognizes CAT tails associated with stalled nascent chains, leading to their ubiquitination and degradation ; [Isoform 4]: Has no E3 ubiquitin-protein ligase activity.
• KEGG Pathway:
  p53 sig.ling pathway (hsa04115)
  Ubiquitin mediated proteolysis (hsa04120)
  Measles (hsa05162)
• Reactome Pathway:
  Antigen processing (R-HSA-983168)
  Translesion Synthesis by POLH (R-HSA-110320)

Molecular Interaction Atlas (MIA) of This DOT

20 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Adenocarcinoma	DIS3IHTY	Strong	Biomarker	[1]
Breast carcinoma	DIS2UE88	Strong	Altered Expression	[2]
Carcinoma	DISH9F1N	Strong	Biomarker	[1]
Head-neck squamous cell carcinoma	DISF7P24	Strong	Altered Expression	[3]
Hepatocellular carcinoma	DIS0J828	Strong	Altered Expression	[4]
Kidney cancer	DISBIPKM	Strong	Altered Expression	[5]
Lung cancer	DISCM4YA	Strong	Biomarker	[6]
Lung neoplasm	DISVARNB	Strong	Biomarker	[6]
Neoplasm	DISZKGEW	Strong	Altered Expression	[2]
Prostate cancer	DISF190Y	Strong	Altered Expression	[7]
Prostate carcinoma	DISMJPLE	Strong	Altered Expression	[7]
Prostate neoplasm	DISHDKGQ	Strong	Biomarker	[7]
Renal carcinoma	DISER9XT	Strong	Altered Expression	[5]
Rheumatoid arthritis	DISTSB4J	Strong	Genetic Variation	[8]
Sciatic neuropathy	DISMGDKX	Strong	Biomarker	[9]
Squamous cell carcinoma	DISQVIFL	Strong	Altered Expression	[1]
Breast cancer	DIS7DPX1	moderate	Altered Expression	[2]
Colon cancer	DISVC52G	moderate	Biomarker	[10]
Colon carcinoma	DISJYKUO	moderate	Biomarker	[10]
Plasma cell myeloma	DIS0DFZ0	moderate	Biomarker	[11]

This DOT Affected the Drug Response of 2 Drug(s)

Drug Name	Drug ID	Highest Status	Interaction	REF
Doxorubicin	DMVP5YE	Approved	RING finger and CHY zinc finger domain-containing protein 1 (RCHY1) decreases the response to substance of Doxorubicin.	[6]
Mitoxantrone	DMM39BF	Approved	RING finger and CHY zinc finger domain-containing protein 1 (RCHY1) affects the response to substance of Mitoxantrone.	[25]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Valproate	DMCFE9I	Approved	Valproate decreases the methylation of RING finger and CHY zinc finger domain-containing protein 1 (RCHY1).	[12]
Arsenic	DMTL2Y1	Approved	Arsenic affects the methylation of RING finger and CHY zinc finger domain-containing protein 1 (RCHY1).	[16]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Ciclosporin	DMAZJFX	Approved	Ciclosporin increases the expression of RING finger and CHY zinc finger domain-containing protein 1 (RCHY1).	[13]
Tretinoin	DM49DUI	Approved	Tretinoin increases the expression of RING finger and CHY zinc finger domain-containing protein 1 (RCHY1).	[14]
Cupric Sulfate	DMP0NFQ	Approved	Cupric Sulfate decreases the expression of RING finger and CHY zinc finger domain-containing protein 1 (RCHY1).	[15]
Arsenic trioxide	DM61TA4	Approved	Arsenic trioxide increases the expression of RING finger and CHY zinc finger domain-containing protein 1 (RCHY1).	[17]
Selenium	DM25CGV	Approved	Selenium decreases the expression of RING finger and CHY zinc finger domain-containing protein 1 (RCHY1).	[18]
Phenobarbital	DMXZOCG	Approved	Phenobarbital affects the expression of RING finger and CHY zinc finger domain-containing protein 1 (RCHY1).	[19]
Tocopherol	DMBIJZ6	Phase 2	Tocopherol decreases the expression of RING finger and CHY zinc finger domain-containing protein 1 (RCHY1).	[18]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A decreases the expression of RING finger and CHY zinc finger domain-containing protein 1 (RCHY1).	[20]
Formaldehyde	DM7Q6M0	Investigative	Formaldehyde decreases the expression of RING finger and CHY zinc finger domain-containing protein 1 (RCHY1).	[21]
Milchsaure	DM462BT	Investigative	Milchsaure decreases the expression of RING finger and CHY zinc finger domain-containing protein 1 (RCHY1).	[22]
QUERCITRIN	DM1DH96	Investigative	QUERCITRIN decreases the expression of RING finger and CHY zinc finger domain-containing protein 1 (RCHY1).	[23]

References

• [1] Regulation of p27 by ubiquitin ligases and its pathological significance in human lung carcinomas.Hum Pathol. 2017 Aug;66:67-78. doi: 10.1016/j.humpath.2017.05.022. Epub 2017 Jun 7.
• [2] Downregulated PIRH2 Can Decrease the Proliferation of Breast Cancer Cells.Arch Med Res. 2016 Apr;47(3):186-95. doi: 10.1016/j.arcmed.2016.06.004. Epub 2016 Jul 6.
• [3] High expression of Pirh2, an E3 ligase for p27, is associated with low expression of p27 and poor prognosis in head and neck cancers.Cancer Sci. 2009 May;100(5):866-72. doi: 10.1111/j.1349-7006.2009.01122.x.
• [4] SCYL1 binding protein 1 promotes the ubiquitin-dependent degradation of Pirh2 and has tumor-suppressive function in the development of hepatocellular carcinoma.Carcinogenesis. 2012 Aug;33(8):1581-8. doi: 10.1093/carcin/bgs162. Epub 2012 May 7.
• [5] High expression of P53-induced Ring-h2 protein is associated with poor prognosis in clear cell renal cell carcinoma.Eur J Surg Oncol. 2013 Jan;39(1):100-6. doi: 10.1016/j.ejso.2012.10.004. Epub 2012 Oct 24.
• [6] E3 ubiquitin ligase Pirh2 enhances tumorigenic properties of human non-small cell lung carcinoma cells. Genes Cancer. 2016 Nov;7(11-12):383-393. doi: 10.18632/genesandcancer.123.
• [7] Human PIRH2 enhances androgen receptor signaling through inhibition of histone deacetylase 1 and is overexpressed in prostate cancer.Mol Cell Biol. 2006 Sep;26(17):6502-10. doi: 10.1128/MCB.00147-06.
• [8] Genome-wide association analysis implicates the involvement of eight loci with response to tocilizumab for the treatment of rheumatoid arthritis.Pharmacogenomics J. 2013 Jun;13(3):235-41. doi: 10.1038/tpj.2012.8. Epub 2012 Apr 10.
• [9] Dynamic changes of PIRH2 and p27kip1 expression in injured rat sciatic nerve.Neurol Sci. 2012 Aug;33(4):749-57. doi: 10.1007/s10072-011-0809-8. Epub 2011 Sep 30.
• [10] Avenanthramide A Induces Cellular Senescence via miR-129-3p/Pirh2/p53 Signaling Pathway To Suppress Colon Cancer Growth.J Agric Food Chem. 2019 May 1;67(17):4808-4816. doi: 10.1021/acs.jafc.9b00833. Epub 2019 Apr 17.
• [11] Pirh2 mediates the sensitivity of myeloma cells to bortezomib via canonical NF-B signaling pathway.Protein Cell. 2018 Sep;9(9):770-784. doi: 10.1007/s13238-017-0500-9. Epub 2018 Feb 13.
• [12] 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.
• [13] Integrating multiple omics to unravel mechanisms of Cyclosporin A induced hepatotoxicity in vitro. Toxicol In Vitro. 2015 Apr;29(3):489-501.
• [14] 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.
• [15] Physiological and toxicological transcriptome changes in HepG2 cells exposed to copper. Physiol Genomics. 2009 Aug 7;38(3):386-401.
• [16] 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.
• [17] Arsenic suppresses cell survival via Pirh2-mediated proteasomal degradation of Np63 protein. J Biol Chem. 2013 Feb 1;288(5):2907-13. doi: 10.1074/jbc.M112.428607. Epub 2012 Dec 27.
• [18] Selenium and vitamin E: cell type- and intervention-specific tissue effects in prostate cancer. J Natl Cancer Inst. 2009 Mar 4;101(5):306-20.
• [19] Reproducible chemical-induced changes in gene expression profiles in human hepatoma HepaRG cells under various experimental conditions. Toxicol In Vitro. 2009 Apr;23(3):466-75. doi: 10.1016/j.tiv.2008.12.018. Epub 2008 Dec 30.
• [20] Bisphenol A induces DSB-ATM-p53 signaling leading to cell cycle arrest, senescence, autophagy, stress response, and estrogen release in human fetal lung fibroblasts. Arch Toxicol. 2018 Apr;92(4):1453-1469.
• [21] Gene expression changes in primary human nasal epithelial cells exposed to formaldehyde in vitro. Toxicol Lett. 2010 Oct 5;198(2):289-95.
• [22] Transcriptional profiling of lactic acid treated reconstructed human epidermis reveals pathways underlying stinging and itch. Toxicol In Vitro. 2019 Jun;57:164-173.
• [23] Molecular mechanisms of quercitrin-induced apoptosis in non-small cell lung cancer. Arch Med Res. 2014 Aug;45(6):445-54.
• [24] E3 ubiquitin ligase Pirh2 enhances tumorigenic properties of human non-small cell lung carcinoma cells. Genes Cancer. 2016 Nov;7(11-12):383-393. doi: 10.18632/genesandcancer.123.
• [25] Gene expression profiling of 30 cancer cell lines predicts resistance towards 11 anticancer drugs at clinically achieved concentrations. Int J Cancer. 2006 Apr 1;118(7):1699-712. doi: 10.1002/ijc.21570.