Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTNN7WYH)

• DOT Name: Hepatoma-derived growth factor-related protein 3 (HDGFL3)
• Synonyms: HRP-3; Hepatoma-derived growth factor 2; HDGF-2
• Gene Name: HDGFL3
• Related Disease:
  Advanced cancer
  Lung cancer
  Lung carcinoma
  Neoplasm
  Hepatocellular carcinoma
  Alcohol dependence
  Bipolar disorder
  Cognitive impairment
• UniProt ID: HDGR3_HUMAN
• PDB ID: 6IIP; 6IIQ; 6IIR; 6IIS; 6IIT
• Pfam ID: PF00855
• Sequence:
  MARPRPREYKAGDLVFAKMKGYPHWPARIDELPEGAVKPPANKYPIFFFGTHETAFLGPK
  DLFPYKEYKDKFGKSNKRKGFNEGLWEIENNPGVKFTGYQAIQQQSSSETEGEGGNTADA
  SSEEEGDRVEEDGKGKRKNEKAGSKRKKSYTSKKSSKQSRKSPGDEDDKDCKEEENKSSS
  EGGDAGNDTRNTTSDLQKTSEGT
• Function: Enhances DNA synthesis and may play a role in cell proliferation.
• Tissue Specificity: Detected in testis, heart, spinal cord and brain.

Molecular Interaction Atlas (MIA) of This DOT

8 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Advanced cancer	DISAT1Z9	Strong	Biomarker	[1]
Lung cancer	DISCM4YA	Strong	Biomarker	[2]
Lung carcinoma	DISTR26C	Strong	Biomarker	[2]
Neoplasm	DISZKGEW	Strong	Biomarker	[1]
Hepatocellular carcinoma	DIS0J828	moderate	Biomarker	[3]
Alcohol dependence	DIS4ZSCO	Limited	Biomarker	[4]
Bipolar disorder	DISAM7J2	Limited	Biomarker	[5]
Cognitive impairment	DISH2ERD	Limited	Biomarker	[6]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Methotrexate	DM2TEOL	Approved	Hepatoma-derived growth factor-related protein 3 (HDGFL3) affects the response to substance of Methotrexate.	[16]
Capecitabine	DMTS85L	Approved	Hepatoma-derived growth factor-related protein 3 (HDGFL3) decreases the response to substance of Capecitabine.	[17]

1 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 Hepatoma-derived growth factor-related protein 3 (HDGFL3).	[7]

8 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 Hepatoma-derived growth factor-related protein 3 (HDGFL3).	[8]
Tretinoin	DM49DUI	Approved	Tretinoin increases the expression of Hepatoma-derived growth factor-related protein 3 (HDGFL3).	[9]
Phenobarbital	DMXZOCG	Approved	Phenobarbital increases the expression of Hepatoma-derived growth factor-related protein 3 (HDGFL3).	[10]
SNDX-275	DMH7W9X	Phase 3	SNDX-275 decreases the expression of Hepatoma-derived growth factor-related protein 3 (HDGFL3).	[11]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene increases the expression of Hepatoma-derived growth factor-related protein 3 (HDGFL3).	[12]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A decreases the expression of Hepatoma-derived growth factor-related protein 3 (HDGFL3).	[13]
Trichostatin A	DM9C8NX	Investigative	Trichostatin A decreases the expression of Hepatoma-derived growth factor-related protein 3 (HDGFL3).	[14]
Lithium chloride	DMHYLQ2	Investigative	Lithium chloride decreases the expression of Hepatoma-derived growth factor-related protein 3 (HDGFL3).	[15]

References

• [1] Insight into the roles of hepatoma derived growth factor related protein-3 under physiological and pathological conditions.Biochem Cell Biol. 2018 Dec;96(6):707-712. doi: 10.1139/bcb-2018-0098. Epub 2018 Aug 3.
• [2] Depletion of hepatoma-derived growth factor-related protein-3 induces apoptotic sensitization of radioresistant A549 cells via reactive oxygen species-dependent p53 activation.Biochem Biophys Res Commun. 2013 Sep 27;439(3):333-9. doi: 10.1016/j.bbrc.2013.08.086. Epub 2013 Sep 6.
• [3] The HRP3 PWWP domain recognizes the minor groove of double-stranded DNA and recruits HRP3 to chromatin.Nucleic Acids Res. 2019 Jun 4;47(10):5436-5448. doi: 10.1093/nar/gkz294.
• [4] SCN11A mRNA levels in female bipolar disorder PBMCs as tentative biomarker for distinct patient sub-phenotypes.Drug Dev Res. 2019 Dec;80(8):1128-1135. doi: 10.1002/ddr.21598. Epub 2019 Sep 9.
• [5] RNA sequencing of bipolar disorder lymphoblastoid cell lines implicates the neurotrophic factor HRP-3 in lithium's clinical efficacy.World J Biol Psychiatry. 2019 Jul;20(6):449-461. doi: 10.1080/15622975.2017.1372629. Epub 2017 Sep 22.
• [6] Recurrent microdeletions of 15q25.2 are associated with increased risk of congenital diaphragmatic hernia, cognitive deficits and possibly Diamond--Blackfan anaemia.J Med Genet. 2010 Nov;47(11):777-81. doi: 10.1136/jmg.2009.075903. Epub 2010 Oct 4.
• [7] 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.
• [8] Comparison of HepG2 and HepaRG by whole-genome gene expression analysis for the purpose of chemical hazard identification. Toxicol Sci. 2010 May;115(1):66-79.
• [9] Phenotypic characterization of retinoic acid differentiated SH-SY5Y cells by transcriptional profiling. PLoS One. 2013 May 28;8(5):e63862.
• [10] Dose- and time-dependent effects of phenobarbital on gene expression profiling in human hepatoma HepaRG cells. Toxicol Appl Pharmacol. 2009 Feb 1;234(3):345-60.
• [11] Definition of transcriptome-based indices for quantitative characterization of chemically disturbed stem cell development: introduction of the STOP-Toxukn and STOP-Toxukk tests. Arch Toxicol. 2017 Feb;91(2):839-864.
• [12] Identification of a transcriptomic signature of food-relevant genotoxins in human HepaRG hepatocarcinoma cells. Food Chem Toxicol. 2020 Jun;140:111297. doi: 10.1016/j.fct.2020.111297. Epub 2020 Mar 28.
• [13] 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.
• [14] 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.
• [15] Early gene response in lithium chloride induced apoptosis. Apoptosis. 2005 Jan;10(1):75-90. doi: 10.1007/s10495-005-6063-x.
• [16] 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.
• [17] Gene expression analysis using human cancer xenografts to identify novel predictive marker genes for the efficacy of 5-fluorouracil-based drugs. Cancer Sci. 2006 Jun;97(6):510-22. doi: 10.1111/j.1349-7006.2006.00204.x.