Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTWG1WIH)

• DOT Name: Periphilin-1 (PPHLN1)
• Synonyms: CDC7 expression repressor; CR; Gastric cancer antigen Ga50
• Gene Name: PPHLN1
• Related Disease: Intrahepatic cholangiocarcinoma
• UniProt ID: PPHLN_HUMAN
• PDB ID: 6SWG
• Pfam ID: PF11488
• Sequence:
  MWSEGRYEYERIPRERAPPRSHPSDGYNRLVNIVPKKPPLLDRPGEGSYNRYYSHVDYRD
  YDEGRSFSHDRRSGPPHRGDESGYRWTRDDHSASRQPEYRDMRDGFRRKSFYSSHYARER
  SPYKRDNTFFRESPVGRKDSPHSRSGSSVSSRSYSPERSKSYSFHQSQHRKSVRPGASYK
  RQNEGNPERDKERPVQSLKTSRDTSPSSGSAVSSSKVLDKPSRLTEKELAEAASKWAAEK
  LEKSDESNLPEISEYEAGSTAPLFTDQPEEPESNTTHGIELFEDSQLTTRSKAIASKTKE
  IEQVYRQDCETFGMVVKMLIEKDPSLEKSIQFALRQNLHEIESAGQTWQQVPPVRNTEMD
  HDGTPENEGEETAQSAPQPPQAPQPLQPRKKRVRRTTQLRRTTGAPDITWGMLKKTTQEA
  ERILLRTQTPFTPENLFLAMLSVVHCNSRKDVKPENKQ
• Function: Component of the HUSH complex, a multiprotein complex that mediates epigenetic repression. The HUSH complex is recruited to genomic loci rich in H3K9me3 and is probably required to maintain transcriptional silencing by promoting recruitment of SETDB1, a histone methyltransferase that mediates further deposition of H3K9me3. In the HUSH complex, contributes to the maintenance of the complex at chromatin. Acts as a transcriptional corepressor and regulates the cell cycle, probably via the HUSH complex. The HUSH complex is also involved in the silencing of unintegrated retroviral DNA: some part of the retroviral DNA formed immediately after infection remains unintegrated in the host genome and is transcriptionally repressed. May be involved in epithelial differentiation by contributing to epidermal integrity and barrier formation.
• Tissue Specificity: Ubiquitous.

Molecular Interaction Atlas (MIA) of This DOT

1 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Intrahepatic cholangiocarcinoma	DIS6GOC8	Strong	Genetic Variation	[1]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Valproate	DMCFE9I	Approved	Valproate increases the expression of Periphilin-1 (PPHLN1).	[2]
Ivermectin	DMDBX5F	Approved	Ivermectin decreases the expression of Periphilin-1 (PPHLN1).	[3]
Diethylstilbestrol	DMN3UXQ	Approved	Diethylstilbestrol decreases the expression of Periphilin-1 (PPHLN1).	[6]
[3H]methyltrienolone	DMTSGOW	Investigative	[3H]methyltrienolone increases the expression of Periphilin-1 (PPHLN1).	[10]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Arsenic	DMTL2Y1	Approved	Arsenic affects the methylation of Periphilin-1 (PPHLN1).	[4]
Quercetin	DM3NC4M	Approved	Quercetin decreases the phosphorylation of Periphilin-1 (PPHLN1).	[5]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene increases the methylation of Periphilin-1 (PPHLN1).	[7]
TAK-243	DM4GKV2	Phase 1	TAK-243 decreases the sumoylation of Periphilin-1 (PPHLN1).	[8]
PMID28870136-Compound-52	DMFDERP	Patented	PMID28870136-Compound-52 affects the phosphorylation of Periphilin-1 (PPHLN1).	[5]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A decreases the methylation of Periphilin-1 (PPHLN1).	[9]
Coumarin	DM0N8ZM	Investigative	Coumarin affects the phosphorylation of Periphilin-1 (PPHLN1).	[5]

References

• [1] Massive parallel sequencing uncovers actionable FGFR2-PPHLN1 fusion and ARAF mutations in intrahepatic cholangiocarcinoma.Nat Commun. 2015 Jan 22;6:6087. doi: 10.1038/ncomms7087.
• [2] Human embryonic stem cell-derived test systems for developmental neurotoxicity: a transcriptomics approach. Arch Toxicol. 2013 Jan;87(1):123-43.
• [3] 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.
• [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] 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.
• [6] Identification of biomarkers and outcomes of endocrine disruption in human ovarian cortex using In Vitro Models. Toxicology. 2023 Feb;485:153425. doi: 10.1016/j.tox.2023.153425. Epub 2023 Jan 5.
• [7] 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.
• [8] 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.
• [9] 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.
• [10] Analysis of the prostate cancer cell line LNCaP transcriptome using a sequencing-by-synthesis approach. BMC Genomics. 2006 Sep 29;7:246. doi: 10.1186/1471-2164-7-246.