Details of Drug Off-Target (DOT)

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

• DOT Name: Protein lin-28 homolog A (LIN28A)
• Synonyms: Lin-28A; Zinc finger CCHC domain-containing protein 1
• Gene Name: LIN28A
• UniProt ID: LN28A_HUMAN
• PDB ID: 2CQF; 2LI8; 5UDZ
• Pfam ID: PF00313 ; PF00098
• Sequence:
  MGSVSNQQFAGGCAKAAEEAPEEAPEDAARAADEPQLLHGAGICKWFNVRMGFGFLSMTA
  RAGVALDPPVDVFVHQSKLHMEGFRSLKEGEAVEFTFKKSAKGLESIRVTGPGGVFCIGS
  ERRPKGKSMQKRRSKGDRCYNCGGLDHHAKECKLPPQPKKCHFCQSISHMVASCPLKAQQ
  GPSAQGKPTYFREEEEEIHSPTLLPEAQN
• Function: RNA-binding protein that inhibits processing of pre-let-7 miRNAs and regulates translation of mRNAs that control developmental timing, pluripotency and metabolism. Seems to recognize a common structural G-quartet (G4) feature in its miRNA and mRNA targets (Probable). 'Translational enhancer' that drives specific mRNAs to polysomes and increases the efficiency of protein synthesis. Its association with the translational machinery and target mRNAs results in an increased number of initiation events per molecule of mRNA and, indirectly, in mRNA stabilization. Binds IGF2 mRNA, MYOD1 mRNA, ARBP/36B4 ribosomal protein mRNA and its own mRNA. Essential for skeletal muscle differentiation program through the translational up-regulation of IGF2 expression. Suppressor of microRNA (miRNA) biogenesis, including that of let-7, miR107, miR-143 and miR-200c. Specifically binds the miRNA precursors (pre-miRNAs), recognizing an 5'-GGAG-3' motif found in pre-miRNA terminal loop, and recruits TUT4 and TUT7 uridylyltransferases. This results in the terminal uridylation of target pre-miRNAs. Uridylated pre-miRNAs fail to be processed by Dicer and undergo degradation. The repression of let-7 expression is required for normal development and contributes to maintain the pluripotent state by preventing let-7-mediated differentiation of embryonic stem cells. Localized to the periendoplasmic reticulum area, binds to a large number of spliced mRNAs and inhibits the translation of mRNAs destined for the ER, reducing the synthesis of transmembrane proteins, ER or Golgi lumen proteins, and secretory proteins. Binds to and enhances the translation of mRNAs for several metabolic enzymes, such as PFKP, PDHA1 or SDHA, increasing glycolysis and oxidative phosphorylation. Which, with the let-7 repression may enhance tissue repair in adult tissue.
• Tissue Specificity: Expressed in embryonic stem cells, placenta and testis. Tends to be up-regulated in HER2-overexpressing breast tumors.
• Reactome Pathway: Transcriptional regulation of pluripotent stem cells (R-HSA-452723)

Molecular Interaction Atlas (MIA) of This DOT

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Valproate	DMCFE9I	Approved	Valproate decreases the expression of Protein lin-28 homolog A (LIN28A).	[1]
Tretinoin	DM49DUI	Approved	Tretinoin decreases the expression of Protein lin-28 homolog A (LIN28A).	[2]
Arsenic	DMTL2Y1	Approved	Arsenic increases the expression of Protein lin-28 homolog A (LIN28A).	[3]
Triclosan	DMZUR4N	Approved	Triclosan decreases the expression of Protein lin-28 homolog A (LIN28A).	[4]
Carbamazepine	DMZOLBI	Approved	Carbamazepine decreases the expression of Protein lin-28 homolog A (LIN28A).	[5]
Decitabine	DMQL8XJ	Approved	Decitabine increases the expression of Protein lin-28 homolog A (LIN28A).	[6]
Lamotrigine	DM8SXYG	Approved	Lamotrigine decreases the expression of Protein lin-28 homolog A (LIN28A).	[5]
Napabucasin	DMDZ6Q3	Phase 3	Napabucasin decreases the expression of Protein lin-28 homolog A (LIN28A).	[7]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene increases the methylation of Protein lin-28 homolog A (LIN28A).	[8]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A decreases the methylation of Protein lin-28 homolog A (LIN28A).	[9]

References

• [1] Human embryonic stem cell-derived test systems for developmental neurotoxicity: a transcriptomics approach. Arch Toxicol. 2013 Jan;87(1):123-43.
• [2] 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.
• [3] [Expression changes of tumor-related gene mRNA in workers who smelt arsenic]. Wei Sheng Yan Jiu. 2018 Jul;47(4):577-587.
• [4] Transcriptome and DNA methylome dynamics during triclosan-induced cardiomyocyte differentiation toxicity. Stem Cells Int. 2018 Oct 29;2018:8608327.
• [5] Antiepileptic drugs are endocrine disruptors for the human fetal testis ex vivo. Toxicol Sci. 2023 Sep 28;195(2):169-183. doi: 10.1093/toxsci/kfad076.
• [6] MeCP2 suppresses LIN28A expression via binding to its methylated-CpG islands in pancreatic cancer cells. Oncotarget. 2016 Mar 22;7(12):14476-85. doi: 10.18632/oncotarget.7507.
• [7] Suppression of cancer relapse and metastasis by inhibiting cancer stemness. Proc Natl Acad Sci U S A. 2015 Feb 10;112(6):1839-44. doi: 10.1073/pnas.1424171112. Epub 2015 Jan 20.
• [8] 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.
• [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.