Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTNL1O2O)

• DOT Name: Metal-response element-binding transcription factor 2 (MTF2)
• Synonyms: Metal regulatory transcription factor 2; Metal-response element DNA-binding protein M96; Polycomb-like protein 2; hPCl2
• Gene Name: MTF2
• Related Disease:
  Acute myelogenous leukaemia
  Advanced cancer
  Neoplasm
  Plasma cell myeloma
• UniProt ID: MTF2_HUMAN
• PDB ID: 5XFR
• Pfam ID: PF14061 ; PF00628 ; PF18104
• Sequence:
  MRDSTGAGNSLVHKRSPLRRNQKTPTSLTKLSLQDGHKAKKPACKFEEGQDVLARWSDGL
  FYLGTIKKINILKQSCFIIFEDSSKSWVLWKDIQTGATGSGEMVCTICQEEYSEAPNEMV
  ICDKCGQGYHQLCHTPHIDSSVIDSDEKWLCRQCVFATTTKRGGALKKGPNAKALQVMKQ
  TLPYSVADLEWDAGHKTNVQQCYCYCGGPGDWYLKMLQCCKCKQWFHEACVQCLQKPMLF
  GDRFYTFICSVCSSGPEYLKRLPLQWVDIAHLCLYNLSVIHKKKYFDSELELMTYINENW
  DRLHPGELADTPKSERYEHVLEALNDYKTMFMSGKEIKKKKHLFGLRIRVPPVPPNVAFK
  AEKEPEGTSHEFKIKGRKASKPISDSREVSNGIEKKGKKKSVGRPPGPYTRKMIQKTAEP
  LLDKESISENPTLDLPCSIGRTEGTAHSSNTSDVDFTGASSAKETTSSSISRHYGLSDSR
  KRTRTGRSWPAAIPHLRRRRGRLPRRALQTQNSEIVKDDEGKEDYQFDELNTEILNNLAD
  QELQLNHLKNSITSYFGAAGRIACGEKYRVLARRVTLDGKVQYLVEWEGATAS
• Function: Polycomb group (PcG) protein that specifically binds histone H3 trimethylated at 'Lys-36' (H3K36me3) and recruits the PRC2 complex, thus enhancing PRC2 H3K27me3 methylation activity. Regulates the transcriptional networks during embryonic stem cell self-renewal and differentiation. Promotes recruitment of the PRC2 complex to the inactive X chromosome in differentiating XX ES cells and PRC2 recruitment to target genes in undifferentiated ES cells. Required to repress Hox genes by enhancing H3K27me3 methylation of the PRC2 complex. In some conditions may act as an inhibitor of PRC2 activity: able to activate the CDKN2A gene and promote cellular senescence by suppressing the catalytic activity of the PRC2 complex locally. Binds to the metal-regulating-element (MRE) of MT1A gene promoter.
• KEGG Pathway: Polycomb repressive complex (hsa03083)
• Reactome Pathway: PRC2 methylates histones and DNA (R-HSA-212300)

Molecular Interaction Atlas (MIA) of This DOT

4 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Acute myelogenous leukaemia	DISCSPTN	Strong	Biomarker	[1]
Advanced cancer	DISAT1Z9	Strong	Biomarker	[1]
Neoplasm	DISZKGEW	Strong	Biomarker	[1]
Plasma cell myeloma	DIS0DFZ0	Strong	Biomarker	[2]

This DOT Affected the Drug Response of 1 Drug(s)

Drug Name	Drug ID	Highest Status	Interaction	REF
Arsenic trioxide	DM61TA4	Approved	Metal-response element-binding transcription factor 2 (MTF2) increases the response to substance of Arsenic trioxide.	[14]

4 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 Metal-response element-binding transcription factor 2 (MTF2).	[3]
Arsenic	DMTL2Y1	Approved	Arsenic affects the methylation of Metal-response element-binding transcription factor 2 (MTF2).	[4]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene decreases the methylation of Metal-response element-binding transcription factor 2 (MTF2).	[9]
TAK-243	DM4GKV2	Phase 1	TAK-243 increases the sumoylation of Metal-response element-binding transcription factor 2 (MTF2).	[10]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Temozolomide	DMKECZD	Approved	Temozolomide increases the expression of Metal-response element-binding transcription factor 2 (MTF2).	[5]
Selenium	DM25CGV	Approved	Selenium decreases the expression of Metal-response element-binding transcription factor 2 (MTF2).	[6]
Progesterone	DMUY35B	Approved	Progesterone increases the expression of Metal-response element-binding transcription factor 2 (MTF2).	[7]
Amphotericin B	DMTAJQE	Approved	Amphotericin B decreases the expression of Metal-response element-binding transcription factor 2 (MTF2).	[8]
Tocopherol	DMBIJZ6	Phase 2	Tocopherol decreases the expression of Metal-response element-binding transcription factor 2 (MTF2).	[6]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A decreases the expression of Metal-response element-binding transcription factor 2 (MTF2).	[11]
Formaldehyde	DM7Q6M0	Investigative	Formaldehyde decreases the expression of Metal-response element-binding transcription factor 2 (MTF2).	[12]
Deguelin	DMXT7WG	Investigative	Deguelin increases the expression of Metal-response element-binding transcription factor 2 (MTF2).	[13]

References

• [1] Targeting the MTF2-MDM2 Axis Sensitizes Refractory Acute Myeloid Leukemia to Chemotherapy.Cancer Discov. 2018 Nov;8(11):1376-1389. doi: 10.1158/2159-8290.CD-17-0841. Epub 2018 Aug 16.
• [2] Anti-CD40 antibody binding modulates human multiple myeloma clonogenicity in vitro.Blood. 1994 Nov 1;84(9):3026-33.
• [3] 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.
• [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] 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.
• [6] 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.
• [7] Coordinate up-regulation of TMEM97 and cholesterol biosynthesis genes in normal ovarian surface epithelial cells treated with progesterone: implications for pathogenesis of ovarian cancer. BMC Cancer. 2007 Dec 11;7:223.
• [8] Differential expression of microRNAs and their predicted targets in renal cells exposed to amphotericin B and its complex with copper (II) ions. Toxicol Mech Methods. 2017 Sep;27(7):537-543. doi: 10.1080/15376516.2017.1333554. Epub 2017 Jun 8.
• [9] 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.
• [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] 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.
• [12] Gene expression changes in primary human nasal epithelial cells exposed to formaldehyde in vitro. Toxicol Lett. 2010 Oct 5;198(2):289-95.
• [13] Neurotoxicity and underlying cellular changes of 21 mitochondrial respiratory chain inhibitors. Arch Toxicol. 2021 Feb;95(2):591-615. doi: 10.1007/s00204-020-02970-5. Epub 2021 Jan 29.
• [14] The NRF2-mediated oxidative stress response pathway is associated with tumor cell resistance to arsenic trioxide across the NCI-60 panel. BMC Med Genomics. 2010 Aug 13;3:37. doi: 10.1186/1755-8794-3-37.