Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OT54KJG6)

• DOT Name: Transmembrane protein 45A (TMEM45A)
• Synonyms: DNA polymerase-transactivated protein 4; Dermal papilla-derived protein 7
• Gene Name: TMEM45A
• Related Disease:
  Advanced cancer
  Clear cell renal carcinoma
  Epithelial ovarian cancer
  Glioma
  Head-neck squamous cell carcinoma
  Kidney cancer
  Lung cancer
  Lung neoplasm
  Neoplasm
  Ovarian cancer
  Ovarian neoplasm
  Renal carcinoma
  Renal cell carcinoma
  Breast cancer
  Breast carcinoma
  Colorectal carcinoma
  Renal fibrosis
• UniProt ID: TM45A_HUMAN
• PDB ID: 7OQZ
• Pfam ID: PF04819
• Sequence:
  MGNFRGHALPGTFFFIIGLWWCTKSILKYICKKQKRTCYLGSKTLFYRLEILEGITIVGM
  ALTGMAGEQFIPGGPHLMLYDYKQGHWNQLLGWHHFTMYFFFGLLGVADILCFTISSLPV
  SLTKLMLSNALFVEAFIFYNHTHGREMLDIFVHQLLVLVVFLTGLVAFLEFLVRNNVLLE
  LLRSSLILLQGSWFFQIGFVLYPPSGGPAWDLMDHENILFLTICFCWHYAVTIVIVGMNY
  AFITWLVKSRLKRLCSSEVGLLKNAEREQESEEEM

Molecular Interaction Atlas (MIA) of This DOT

17 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Advanced cancer	DISAT1Z9	Strong	Biomarker	[1]
Clear cell renal carcinoma	DISBXRFJ	Strong	Altered Expression	[1]
Epithelial ovarian cancer	DIS56MH2	Strong	Altered Expression	[2]
Glioma	DIS5RPEH	Strong	Altered Expression	[3]
Head-neck squamous cell carcinoma	DISF7P24	Strong	Altered Expression	[1]
Kidney cancer	DISBIPKM	Strong	Altered Expression	[1]
Lung cancer	DISCM4YA	Strong	Biomarker	[4]
Lung neoplasm	DISVARNB	Strong	Biomarker	[4]
Neoplasm	DISZKGEW	Strong	Altered Expression	[3]
Ovarian cancer	DISZJHAP	Strong	Altered Expression	[2]
Ovarian neoplasm	DISEAFTY	Strong	Altered Expression	[2]
Renal carcinoma	DISER9XT	Strong	Altered Expression	[1]
Renal cell carcinoma	DISQZ2X8	Strong	Altered Expression	[1]
Breast cancer	DIS7DPX1	moderate	Altered Expression	[5]
Breast carcinoma	DIS2UE88	moderate	Altered Expression	[5]
Colorectal carcinoma	DIS5PYL0	moderate	Altered Expression	[6]
Renal fibrosis	DISMHI3I	moderate	Biomarker	[7]

3 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 Transmembrane protein 45A (TMEM45A).	[8]
Arsenic	DMTL2Y1	Approved	Arsenic increases the ubiquitination of Transmembrane protein 45A (TMEM45A).	[16]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene decreases the methylation of Transmembrane protein 45A (TMEM45A).	[26]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Ciclosporin	DMAZJFX	Approved	Ciclosporin decreases the expression of Transmembrane protein 45A (TMEM45A).	[9]
Tretinoin	DM49DUI	Approved	Tretinoin decreases the expression of Transmembrane protein 45A (TMEM45A).	[10]
Acetaminophen	DMUIE76	Approved	Acetaminophen affects the expression of Transmembrane protein 45A (TMEM45A).	[11]
Doxorubicin	DMVP5YE	Approved	Doxorubicin decreases the expression of Transmembrane protein 45A (TMEM45A).	[12]
Cupric Sulfate	DMP0NFQ	Approved	Cupric Sulfate decreases the expression of Transmembrane protein 45A (TMEM45A).	[13]
Cisplatin	DMRHGI9	Approved	Cisplatin decreases the expression of Transmembrane protein 45A (TMEM45A).	[14]
Estradiol	DMUNTE3	Approved	Estradiol increases the expression of Transmembrane protein 45A (TMEM45A).	[15]
Quercetin	DM3NC4M	Approved	Quercetin decreases the expression of Transmembrane protein 45A (TMEM45A).	[17]
Hydrogen peroxide	DM1NG5W	Approved	Hydrogen peroxide affects the expression of Transmembrane protein 45A (TMEM45A).	[18]
Phenobarbital	DMXZOCG	Approved	Phenobarbital affects the expression of Transmembrane protein 45A (TMEM45A).	[19]
Progesterone	DMUY35B	Approved	Progesterone increases the expression of Transmembrane protein 45A (TMEM45A).	[20]
Niclosamide	DMJAGXQ	Approved	Niclosamide increases the expression of Transmembrane protein 45A (TMEM45A).	[21]
Cytarabine	DMZD5QR	Approved	Cytarabine decreases the expression of Transmembrane protein 45A (TMEM45A).	[22]
Amphotericin B	DMTAJQE	Approved	Amphotericin B decreases the expression of Transmembrane protein 45A (TMEM45A).	[23]
Lucanthone	DMZLBUO	Approved	Lucanthone increases the expression of Transmembrane protein 45A (TMEM45A).	[24]
Urethane	DM7NSI0	Phase 4	Urethane decreases the expression of Transmembrane protein 45A (TMEM45A).	[25]
(+)-JQ1	DM1CZSJ	Phase 1	(+)-JQ1 decreases the expression of Transmembrane protein 45A (TMEM45A).	[27]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A affects the expression of Transmembrane protein 45A (TMEM45A).	[28]
Trichostatin A	DM9C8NX	Investigative	Trichostatin A increases the expression of Transmembrane protein 45A (TMEM45A).	[29]
Nickel chloride	DMI12Y8	Investigative	Nickel chloride increases the expression of Transmembrane protein 45A (TMEM45A).	[30]

References

• [1] Characterization of the role of TMEM45A in cancer cell sensitivity to cisplatin.Cell Death Dis. 2019 Dec 4;10(12):919. doi: 10.1038/s41419-019-2088-x.
• [2] Inhibition of TMEM45A suppresses proliferation, induces cell cycle arrest and reduces cell invasion in human ovarian cancer cells.Oncol Rep. 2015 Jun;33(6):3124-30. doi: 10.3892/or.2015.3902. Epub 2015 Apr 7.
• [3] Knockdown of TMEM45A inhibits the proliferation, migration and invasion of glioma cells.Int J Clin Exp Pathol. 2015 Oct 1;8(10):12657-67. eCollection 2015.
• [4] Bronchial airway gene expression signatures in mouse lung squamous cell carcinoma and their modulation by cancer chemopreventive agents.Oncotarget. 2017 Mar 21;8(12):18885-18900. doi: 10.18632/oncotarget.13806.
• [5] TMEM45A is essential for hypoxia-induced chemoresistance in breast and liver cancer cells.BMC Cancer. 2012 Sep 6;12:391. doi: 10.1186/1471-2407-12-391.
• [6] Knockdown of TMEM45A overcomes multidrug resistance and epithelial-mesenchymal transition in human colorectal cancer cells through inhibition of TGF- signalling pathway.Clin Exp Pharmacol Physiol. 2020 Mar;47(3):503-516. doi: 10.1111/1440-1681.13220. Epub 2019 Dec 29.
• [7] TMEM45A is involved in renal fibrosis in rats by regulating Jagged1/Notch pathway.Front Biosci (Landmark Ed). 2020 Jan 1;25(4):593-605. doi: 10.2741/4823.
• [8] 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.
• [9] Integrating multiple omics to unravel mechanisms of Cyclosporin A induced hepatotoxicity in vitro. Toxicol In Vitro. 2015 Apr;29(3):489-501.
• [10] Development of a neural teratogenicity test based on human embryonic stem cells: response to retinoic acid exposure. Toxicol Sci. 2011 Dec;124(2):370-7.
• [11] Gene expression analysis of precision-cut human liver slices indicates stable expression of ADME-Tox related genes. Toxicol Appl Pharmacol. 2011 May 15;253(1):57-69.
• [12] 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.
• [13] Physiological and toxicological transcriptome changes in HepG2 cells exposed to copper. Physiol Genomics. 2009 Aug 7;38(3):386-401.
• [14] Transcriptomics hit the target: monitoring of ligand-activated and stress response pathways for chemical testing. Toxicol In Vitro. 2015 Dec 25;30(1 Pt A):7-18.
• [15] Long-term estrogen exposure promotes carcinogen bioactivation, induces persistent changes in gene expression, and enhances the tumorigenicity of MCF-7 human breast cancer cells. Toxicol Appl Pharmacol. 2009 Nov 1;240(3):355-66.
• [16] Quantitative Assessment of Arsenite-Induced Perturbation of Ubiquitinated Proteome. Chem Res Toxicol. 2022 Sep 19;35(9):1589-1597. doi: 10.1021/acs.chemrestox.2c00197. Epub 2022 Aug 22.
• [17] Comparison of phenotypic and transcriptomic effects of false-positive genotoxins, true genotoxins and non-genotoxins using HepG2 cells. Mutagenesis. 2011 Sep;26(5):593-604.
• [18] 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.
• [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] Endometrial receptivity is affected in women with high circulating progesterone levels at the end of the follicular phase: a functional genomics analysis. Hum Reprod. 2011 Jul;26(7):1813-25.
• [21] 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.
• [22] Cytosine arabinoside induces ectoderm and inhibits mesoderm expression in human embryonic stem cells during multilineage differentiation. Br J Pharmacol. 2011 Apr;162(8):1743-56.
• [23] 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.
• [24] Lucanthone is a novel inhibitor of autophagy that induces cathepsin D-mediated apoptosis. J Biol Chem. 2011 Feb 25;286(8):6602-13.
• [25] Ethyl carbamate induces cell death through its effects on multiple metabolic pathways. Chem Biol Interact. 2017 Nov 1;277:21-32.
• [26] 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.
• [27] Inhibition of BRD4 attenuates tumor cell self-renewal and suppresses stem cell signaling in MYC driven medulloblastoma. Oncotarget. 2014 May 15;5(9):2355-71.
• [28] Comprehensive analysis of transcriptomic changes induced by low and high doses of bisphenol A in HepG2 spheroids in vitro and rat liver in vivo. Environ Res. 2019 Jun;173:124-134. doi: 10.1016/j.envres.2019.03.035. Epub 2019 Mar 18.
• [29] From transient transcriptome responses to disturbed neurodevelopment: role of histone acetylation and methylation as epigenetic switch between reversible and irreversible drug effects. Arch Toxicol. 2014 Jul;88(7):1451-68.
• [30] Effects of nickel treatment on H3K4 trimethylation and gene expression. PLoS One. 2011 Mar 24;6(3):e17728. doi: 10.1371/journal.pone.0017728.