Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTWX2GHS)

• DOT Name: Hepatoma-derived growth factor-related protein 2 (HDGFL2)
• Synonyms: HDGF-related protein 2; HRP-2; Hepatoma-derived growth factor 2; HDGF-2
• Gene Name: HDGFL2
• Related Disease:
  Hepatitis B virus infection
  Hepatocellular carcinoma
  Neoplasm
  Smallpox
  Plasmodium falciparum malaria
  Retinopathy
  Acute myelogenous leukaemia
  Gonorrhea
• UniProt ID: HDGR2_HUMAN
• PDB ID: 3EAE; 3QBY; 3QJ6; 6T3I
• Pfam ID: PF11467 ; PF00855
• Sequence:
  MPHAFKPGDLVFAKMKGYPHWPARIDDIADGAVKPPPNKYPIFFFGTHETAFLGPKDLFP
  YDKCKDKYGKPNKRKGFNEGLWEIQNNPHASYSAPPPVSSSDSEAPEANPADGSDADEDD
  EDRGVMAVTAVTATAASDRMESDSDSDKSSDNSGLKRKTPALKMSVSKRARKASSDLDQA
  SVSPSEEENSESSSESEKTSDQDFTPEKKAAVRAPRRGPLGGRKKKKAPSASDSDSKADS
  DGAKPEPVAMARSASSSSSSSSSSDSDVSVKKPPRGRKPAEKPLPKPRGRKPKPERPPSS
  SSSDSDSDEVDRISEWKRRDEARRRELEARRRREQEEELRRLREQEKEEKERRRERADRG
  EAERGSGGSSGDELREDDEPVKKRGRKGRGRGPPSSSDSEPEAELEREAKKSAKKPQSSS
  TEPARKPGQKEKRVRPEEKQQAKPVKVERTRKRSEGFSMDRKVEKKKEPSVEEKLQKLHS
  EIKFALKVDSPDVKRCLNALEELGTLQVTSQILQKNTDVVATLKKIRRYKANKDVMEKAA
  EVYTRLKSRVLGPKIEAVQKVNKAGMEKEKAEEKLAGEELAGEEAPQEKAEDKPSTDLSA
  PVNGEATSQKGESAEDKEHEEGRDSEEGPRCGSSEDLHDSVREGPDLDRPGSDRQERERA
  RGDSEALDEES
• Function: Acts as an epigenetic regulator of myogenesis in cooperation with DPF3a (isoform 2 of DPF3/BAF45C). Associates with the BAF complex via its interaction with DPF3a and HDGFL2-DPF3a activate myogenic genes by increasing chromatin accessibility through recruitment of SMARCA4/BRG1/BAF190A (ATPase subunit of the BAF complex) to myogenic gene promoters. Promotes the repair of DNA double-strand breaks (DSBs) through the homologous recombination pathway by facilitating the recruitment of the DNA endonuclease RBBP8 to the DSBs. Preferentially binds to chromatin regions marked by H3K9me3, H3K27me3 and H3K36me2. Involved in cellular growth control, through the regulation of cyclin D1 expression.
• Tissue Specificity: Widely expressed. High expression is found in heart, skeletal muscle, ovary and testis. Overexpression is frequently observed in hepatocellular carcinoma samples.

Molecular Interaction Atlas (MIA) of This DOT

8 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Hepatitis B virus infection	DISLQ2XY	Strong	Biomarker	[1]
Hepatocellular carcinoma	DIS0J828	Strong	Biomarker	[2]
Neoplasm	DISZKGEW	Strong	Biomarker	[2]
Smallpox	DIS9EABZ	Strong	Genetic Variation	[3]
Plasmodium falciparum malaria	DIS3Q9KF	moderate	Altered Expression	[4]
Retinopathy	DISB4B0F	moderate	Biomarker	[5]
Acute myelogenous leukaemia	DISCSPTN	Limited	Genetic Variation	[6]
Gonorrhea	DISQ5AO6	Limited	Altered Expression	[7]

5 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 2 (HDGFL2).	[8]
TAK-243	DM4GKV2	Phase 1	TAK-243 increases the sumoylation of Hepatoma-derived growth factor-related protein 2 (HDGFL2).	[10]
PMID28870136-Compound-52	DMFDERP	Patented	PMID28870136-Compound-52 affects the phosphorylation of Hepatoma-derived growth factor-related protein 2 (HDGFL2).	[11]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A decreases the methylation of Hepatoma-derived growth factor-related protein 2 (HDGFL2).	[12]
Coumarin	DM0N8ZM	Investigative	Coumarin affects the phosphorylation of Hepatoma-derived growth factor-related protein 2 (HDGFL2).	[11]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Ivermectin	DMDBX5F	Approved	Ivermectin decreases the expression of Hepatoma-derived growth factor-related protein 2 (HDGFL2).	[9]
Trichostatin A	DM9C8NX	Investigative	Trichostatin A affects the expression of Hepatoma-derived growth factor-related protein 2 (HDGFL2).	[13]

References

• [1] Prevalence of malaria and hepatitis B among pregnant women in Northern Ghana: Comparing RDTs with PCR.PLoS One. 2019 Feb 6;14(2):e0210365. doi: 10.1371/journal.pone.0210365. eCollection 2019.
• [2] HDGF-related protein-2 (HRP-2) acts as an oncogene to promote cell growth in hepatocellular carcinoma.Biochem Biophys Res Commun. 2015 Mar 20;458(4):849-55. doi: 10.1016/j.bbrc.2015.02.042. Epub 2015 Feb 14.
• [3] Protection against lethal vaccinia virus challenge in HLA-A2 transgenic mice by immunization with a single CD8+ T-cell peptide epitope of vaccinia and variola viruses.J Virol. 2004 Jul;78(13):7052-60. doi: 10.1128/JVI.78.13.7052-7060.2004.
• [4] Clearance dynamics of lactate dehydrogenase and aldolase following antimalarial treatment for Plasmodium falciparum infection.Parasit Vectors. 2019 Jun 10;12(1):293. doi: 10.1186/s13071-019-3549-x.
• [5] Plasmodium falciparum Histidine-Rich Protein-2 Plasma Concentrations Are Higher in Retinopathy-Negative Cerebral Malaria Than in Severe Malarial Anemia.Open Forum Infect Dis. 2017 Jul 22;4(3):ofx151. doi: 10.1093/ofid/ofx151. eCollection 2017 Summer.
• [6] Genome-wide haplotype association study identify the FGFR2 gene as a risk gene for acute myeloid leukemia.Oncotarget. 2017 Jan 31;8(5):7891-7899. doi: 10.18632/oncotarget.13631.
• [7] Analysis of key genes and signaling pathways involved in Helicobacter pylori-associated gastric cancer based on The Cancer Genome Atlas database and RNA sequencing data.Helicobacter. 2018 Oct;23(5):e12530. doi: 10.1111/hel.12530. Epub 2018 Sep 2.
• [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] Quantitative proteomics reveals a broad-spectrum antiviral property of ivermectin, benefiting for COVID-19 treatment. J Cell Physiol. 2021 Apr;236(4):2959-2975. doi: 10.1002/jcp.30055. Epub 2020 Sep 22.
• [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] Quantitative phosphoproteomics reveal cellular responses from caffeine, coumarin and quercetin in treated HepG2 cells. Toxicol Appl Pharmacol. 2022 Aug 15;449:116110. doi: 10.1016/j.taap.2022.116110. Epub 2022 Jun 7.
• [12] DNA methylome-wide alterations associated with estrogen receptor-dependent effects of bisphenols in breast cancer. Clin Epigenetics. 2019 Oct 10;11(1):138. doi: 10.1186/s13148-019-0725-y.
• [13] A trichostatin A expression signature identified by TempO-Seq targeted whole transcriptome profiling. PLoS One. 2017 May 25;12(5):e0178302. doi: 10.1371/journal.pone.0178302. eCollection 2017.