Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTITK1XD)

• DOT Name: Runt-related transcription factor 3 (RUNX3)
• Synonyms: Acute myeloid leukemia 2 protein; Core-binding factor subunit alpha-3; CBF-alpha-3; Oncogene AML-2; Polyomavirus enhancer-binding protein 2 alpha C subunit; PEA2-alpha C; PEBP2-alpha C; SL3-3 enhancer factor 1 alpha C subunit; SL3/AKV core-binding factor alpha C subunit
• Gene Name: RUNX3
• UniProt ID: RUNX3_HUMAN
• PDB ID: 5W69
• Pfam ID: PF00853 ; PF08504
• Sequence:
  MRIPVDPSTSRRFTPPSPAFPCGGGGGKMGENSGALSAQAAVGPGGRARPEVRSMVDVLA
  DHAGELVRTDSPNFLCSVLPSHWRCNKTLPVAFKVVALGDVPDGTVVTVMAGNDENYSAE
  LRNASAVMKNQVARFNDLRFVGRSGRGKSFTLTITVFTNPTQVATYHRAIKVTVDGPREP
  RRHRQKLEDQTKPFPDRFGDLERLRMRVTPSTPSPRGSLSTTSHFSSQPQTPIQGTSELN
  PFSDPRQFDRSFPTLPTLTESRFPDPRMHYPGAMSAAFPYSATPSGTSISSLSVAGMPAT
  SRFHHTYLPPPYPGAPQNQSGPFQANPSPYHLYYGTSSGSYQFSMVAGSSSGGDRSPTRM
  LASCTSSAASVAAGNLMNPSLGGQSDGVEADGSHSNSPTALSTPGRMDEAVWRPY
• Function: Forms the heterodimeric complex core-binding factor (CBF) with CBFB. RUNX members modulate the transcription of their target genes through recognizing the core consensus binding sequence 5'-TGTGGT-3', or very rarely, 5'-TGCGGT-3', within their regulatory regions via their runt domain, while CBFB is a non-DNA-binding regulatory subunit that allosterically enhances the sequence-specific DNA-binding capacity of RUNX. The heterodimers bind to the core site of a number of enhancers and promoters, including murine leukemia virus, polyomavirus enhancer, T-cell receptor enhancers, LCK, IL3 and GM-CSF promoters. May be involved in the control of cellular proliferation and/or differentiation. In association with ZFHX3, up-regulates CDKN1A promoter activity following TGF-beta stimulation. CBF complexes repress ZBTB7B transcription factor during cytotoxic (CD8+) T cell development. They bind to RUNX-binding sequence within the ZBTB7B locus acting as transcriptional silencer and allowing for cytotoxic T cell differentiation. CBF complexes binding to the transcriptional silencer is essential for recruitment of nuclear protein complexes that catalyze epigenetic modifications to establish epigenetic ZBTB7B silencing.
• Tissue Specificity: Expressed in gastric cancer tissues (at protein level).
• KEGG Pathway:
  Th1 and Th2 cell differentiation (hsa04658)
  Epstein-Barr virus infection (hsa05169)
• Reactome Pathway:
  RUNX3 regulates CDKN1A transcription (R-HSA-8941855)
  RUNX3 regulates NOTCH signaling (R-HSA-8941856)
  Regulation of RUNX3 expression and activity (R-HSA-8941858)
  RUNX3 Regulates Immune Response and Cell Migration (R-HSA-8949275)
  RUNX3 regulates WNT signaling (R-HSA-8951430)
  RUNX3 regulates YAP1-mediated transcription (R-HSA-8951671)
  RUNX3 regulates RUNX1-mediated transcription (R-HSA-8951911)
  RUNX3 regulates p14-ARF (R-HSA-8951936)
  RUNX3 regulates BCL2L11 (BIM) transcription (R-HSA-8952158)
  Binding of TCF/LEF (R-HSA-4411364)

Molecular Interaction Atlas (MIA) of This DOT

This DOT Affected the Regulation of Drug Effects of 1 Drug(s)

Drug Name	Drug ID	Highest Status	Interaction	REF
Doxorubicin	DMVP5YE	Approved	Runt-related transcription factor 3 (RUNX3) decreases the export of Doxorubicin.	[11]

This DOT Affected the Drug Response of 3 Drug(s)

Drug Name	Drug ID	Highest Status	Interaction	REF
Etoposide	DMNH3PG	Approved	Runt-related transcription factor 3 (RUNX3) increases the response to substance of Etoposide.	[11]
Mitomycin	DMH0ZJE	Approved	Runt-related transcription factor 3 (RUNX3) increases the response to substance of Mitomycin.	[11]
Mitoxantrone	DMM39BF	Approved	Runt-related transcription factor 3 (RUNX3) affects the response to substance of Mitoxantrone.	[12]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Valproate	DMCFE9I	Approved	Valproate increases the methylation of Runt-related transcription factor 3 (RUNX3).	[1]
Arsenic	DMTL2Y1	Approved	Arsenic affects the methylation of Runt-related transcription factor 3 (RUNX3).	[4]
Azacitidine	DMTA5OE	Approved	Azacitidine affects the methylation of Runt-related transcription factor 3 (RUNX3).	[7]
TAK-243	DM4GKV2	Phase 1	TAK-243 increases the sumoylation of Runt-related transcription factor 3 (RUNX3).	[10]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Tretinoin	DM49DUI	Approved	Tretinoin increases the expression of Runt-related transcription factor 3 (RUNX3).	[2]
Cisplatin	DMRHGI9	Approved	Cisplatin decreases the expression of Runt-related transcription factor 3 (RUNX3).	[3]
Decitabine	DMQL8XJ	Approved	Decitabine increases the expression of Runt-related transcription factor 3 (RUNX3).	[5]
Panobinostat	DM58WKG	Approved	Panobinostat increases the expression of Runt-related transcription factor 3 (RUNX3).	[6]
Amphotericin B	DMTAJQE	Approved	Amphotericin B decreases the expression of Runt-related transcription factor 3 (RUNX3).	[3]
Cyclophosphamide	DM4O2Z7	Approved	Cyclophosphamide decreases the expression of Runt-related transcription factor 3 (RUNX3).	[3]
Gentamicin	DMKINJO	Approved	Gentamicin decreases the expression of Runt-related transcription factor 3 (RUNX3).	[3]
SNDX-275	DMH7W9X	Phase 3	SNDX-275 increases the expression of Runt-related transcription factor 3 (RUNX3).	[6]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene increases the expression of Runt-related transcription factor 3 (RUNX3).	[8]
(+)-JQ1	DM1CZSJ	Phase 1	(+)-JQ1 decreases the expression of Runt-related transcription factor 3 (RUNX3).	[9]

References

• [1] Nuclear and Mitochondrial DNA Methylation Patterns Induced by Valproic Acid in Human Hepatocytes. Chem Res Toxicol. 2017 Oct 16;30(10):1847-1854. doi: 10.1021/acs.chemrestox.7b00171. Epub 2017 Sep 13.
• [2] 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.
• [3] Effect of nephrotoxicants and hepatotoxicants on gene expression profile in human peripheral blood mononuclear cells. Biochem Biophys Res Commun. 2010 Oct 15;401(2):245-50. doi: 10.1016/j.bbrc.2010.09.039. Epub 2010 Sep 16.
• [4] 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.
• [5] Chemical genomic screening for methylation-silenced genes in gastric cancer cell lines using 5-aza-2'-deoxycytidine treatment and oligonucleotide microarray. Cancer Sci. 2006 Jan;97(1):64-71.
• [6] A transcriptome-based classifier to identify developmental toxicants by stem cell testing: design, validation and optimization for histone deacetylase inhibitors. Arch Toxicol. 2015 Sep;89(9):1599-618.
• [7] Promoter hypermethylation of the RUNX3 gene in esophageal squamous cell carcinoma. Cancer Invest. 2007 Dec;25(8):685-90. doi: 10.1080/07357900701561131.
• [8] Transcriptional signature of human macrophages exposed to the environmental contaminant benzo(a)pyrene. Toxicol Sci. 2010 Apr;114(2):247-59.
• [9] Bromodomain-containing protein 4 (BRD4) regulates RNA polymerase II serine 2 phosphorylation in human CD4+ T cells. J Biol Chem. 2012 Dec 14;287(51):43137-55.
• [10] 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.
• [11] Tumor suppressor gene Runx3 sensitizes gastric cancer cells to chemotherapeutic drugs by downregulating Bcl-2, MDR-1 and MRP-1. Int J Cancer. 2005 Aug 10;116(1):155-60. doi: 10.1002/ijc.20919.
• [12] 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.