Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTLHW00C)

• DOT Name: Protein lin-9 homolog (LIN9)
• Synonyms: HuLin-9; hLin-9; Beta subunit-associated regulator of apoptosis; TUDOR gene similar protein; Type I interferon receptor beta chain-associated protein; pRB-associated protein
• Gene Name: LIN9
• Related Disease:
  Advanced cancer
  B-cell neoplasm
  Bladder cancer
  Breast cancer
  Breast carcinoma
  Glioma
  Hepatocellular carcinoma
  Neoplasm
  Retinoblastoma
  Triple negative breast cancer
  Tuberculosis
  Urinary bladder cancer
  Urinary bladder neoplasm
  Nervous system disease
• UniProt ID: LIN9_HUMAN
• PDB ID: 6C48; 7N40; 7R1D
• Pfam ID: PF06584 ; PF19438
• Sequence:
  MAELDQLPDESSSAKALVSLKEGSLSNTWNEKYSSLQKTPVWKGRNTSSAVEMPFRNSKR
  SRLFSDEDDRQINTRSPKRNQRVAMVPQKFTATMSTPDKKASQKIGFRLRNLLKLPKAHK
  WCIYEWFYSNIDKPLFEGDNDFCVCLKESFPNLKTRKLTRVEWGKIRRLMGKPRRCSSAF
  FEEERSALKQKRQKIRLLQQRKVADVSQFKDLPDEIPLPLVIGTKVTARLRGVHDGLFTG
  QIDAVDTLNATYRVTFDRTGLGTHTIPDYEVLSNEPHETMPIAAFGQKQRPSRFFMTPPR
  LHYTPPLQSPIIDNDPLLGQSPWRSKISGSDTETLGGFPVEFLIQVTRLSKILMIKKEHI
  KKLREMNTEAEKLKSYSMPISIEFQRRYATIVLELEQLNKDLNKVLHKVQQYCYELAPDQ
  GLQPADQPTDMRRRCEEEAQEIVRHANSSTGQPCVENENLTDLISRLTAILLQIKCLAEG
  GDLNSFEFKSLTDSLNDIKSTIDASNISCFQNNVEIHVAHIQSGLSQMGNLHAFAANNTN
  RD
• Function: Acts as a tumor suppressor. Inhibits DNA synthesis. Its ability to inhibit oncogenic transformation is mediated through its association with RB1. Plays a role in the expression of genes required for the G1/S transition.
• Tissue Specificity: Expressed in thymus and testis.
• KEGG Pathway: Cellular senescence (hsa04218)
• Reactome Pathway:
  Transcription of E2F targets under negative control by p107 (RBL1) and p130 (RBL2) in complex with HDAC1 (R-HSA-1362300)
  G0 and Early G1 (R-HSA-1538133)
  Polo-like kinase mediated events (R-HSA-156711)
  Cyclin E associated events during G1/S transition (R-HSA-69202)
  G1/S-Specific Transcription (R-HSA-69205)
  Cyclin A (R-HSA-69656)
  Transcription of E2F targets under negative control by DREAM complex (R-HSA-1362277)

Molecular Interaction Atlas (MIA) of This DOT

14 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Advanced cancer	DISAT1Z9	Strong	Altered Expression	[1]
B-cell neoplasm	DISVY326	Strong	Biomarker	[2]
Bladder cancer	DISUHNM0	Strong	Altered Expression	[3]
Breast cancer	DIS7DPX1	Strong	Altered Expression	[4]
Breast carcinoma	DIS2UE88	Strong	Altered Expression	[4]
Glioma	DIS5RPEH	Strong	Biomarker	[5]
Hepatocellular carcinoma	DIS0J828	Strong	Altered Expression	[6]
Neoplasm	DISZKGEW	Strong	Biomarker	[5]
Retinoblastoma	DISVPNPB	Strong	Biomarker	[7]
Triple negative breast cancer	DISAMG6N	Strong	Genetic Variation	[1]
Tuberculosis	DIS2YIMD	Strong	Genetic Variation	[8]
Urinary bladder cancer	DISDV4T7	Strong	Altered Expression	[3]
Urinary bladder neoplasm	DIS7HACE	Strong	Posttranslational Modification	[3]
Nervous system disease	DISJ7GGT	Limited	Genetic Variation	[9]

10 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-9 homolog (LIN9).	[10]
Tretinoin	DM49DUI	Approved	Tretinoin decreases the expression of Protein lin-9 homolog (LIN9).	[11]
Cisplatin	DMRHGI9	Approved	Cisplatin increases the expression of Protein lin-9 homolog (LIN9).	[12]
Calcitriol	DM8ZVJ7	Approved	Calcitriol decreases the expression of Protein lin-9 homolog (LIN9).	[13]
Testosterone	DM7HUNW	Approved	Testosterone decreases the expression of Protein lin-9 homolog (LIN9).	[13]
Ethanol	DMDRQZU	Approved	Ethanol decreases the expression of Protein lin-9 homolog (LIN9).	[14]
Lucanthone	DMZLBUO	Approved	Lucanthone decreases the expression of Protein lin-9 homolog (LIN9).	[15]
Urethane	DM7NSI0	Phase 4	Urethane decreases the expression of Protein lin-9 homolog (LIN9).	[16]
(+)-JQ1	DM1CZSJ	Phase 1	(+)-JQ1 decreases the expression of Protein lin-9 homolog (LIN9).	[18]
PMID28460551-Compound-2	DM4DOUB	Patented	PMID28460551-Compound-2 decreases the expression of Protein lin-9 homolog (LIN9).	[19]

4 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-9 homolog (LIN9).	[17]
PMID28870136-Compound-52	DMFDERP	Patented	PMID28870136-Compound-52 affects the phosphorylation of Protein lin-9 homolog (LIN9).	[20]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A increases the methylation of Protein lin-9 homolog (LIN9).	[21]
Coumarin	DM0N8ZM	Investigative	Coumarin increases the phosphorylation of Protein lin-9 homolog (LIN9).	[20]

References

• [1] Mitotic Vulnerability in Triple-Negative Breast Cancer Associated with LIN9 Is Targetable with BET Inhibitors.Cancer Res. 2017 Oct 1;77(19):5395-5408. doi: 10.1158/0008-5472.CAN-17-1571. Epub 2017 Aug 14.
• [2] Ovarian cancer proliferation and apoptosis are regulated by human transfer RNA methyltransferase 9-likevia LIN9.Oncol Lett. 2017 Oct;14(4):4461-4466. doi: 10.3892/ol.2017.6750. Epub 2017 Aug 14.
• [3] Epigenetic repression of regulator of G-protein signaling 2 by ubiquitin-like with PHD and ring-finger domain1 promotes bladder cancer progression.FEBS J. 2015 Jan;282(1):174-82. doi: 10.1111/febs.13116. Epub 2014 Dec 3.
• [4] LIN9 confers paclitaxel resistance in triple negative breast cancer cells by upregulating CCSAP.Sci China Life Sci. 2020 Mar;63(3):419-428. doi: 10.1007/s11427-019-9581-8. Epub 2019 Aug 14.
• [5] Identification of a novel fusion gene HMGA2-EGFR in glioblastoma.Int J Cancer. 2018 Apr 15;142(8):1627-1639. doi: 10.1002/ijc.31179. Epub 2017 Dec 11.
• [6] High MYBL2 expression and transcription regulatory activity is associated with poor overall survival in patients with hepatocellular carcinoma.Curr Res Transl Med. 2018 Mar;66(1):27-32. doi: 10.1016/j.retram.2017.11.002. Epub 2017 Dec 21.
• [7] Inhibition of oncogenic transformation by mammalian Lin-9, a pRB-associated protein.EMBO J. 2004 Nov 24;23(23):4627-38. doi: 10.1038/sj.emboj.7600470. Epub 2004 Nov 11.
• [8] Clinical significance of lnc-AC145676.2.1-6 and lnc-TGS1-1 and their variants in western Chinese tuberculosis patients.Int J Infect Dis. 2019 Jul;84:8-14. doi: 10.1016/j.ijid.2019.04.018. Epub 2019 Apr 24.
• [9] The importance of de novo mutations for pediatric neurological disease--It is not all in utero or birth trauma.Mutat Res Rev Mutat Res. 2016 Jan-Mar;767:42-58. doi: 10.1016/j.mrrev.2015.12.002. Epub 2016 Jan 4.
• [10] Human embryonic stem cell-derived test systems for developmental neurotoxicity: a transcriptomics approach. Arch Toxicol. 2013 Jan;87(1):123-43.
• [11] Transcriptional and Metabolic Dissection of ATRA-Induced Granulocytic Differentiation in NB4 Acute Promyelocytic Leukemia Cells. Cells. 2020 Nov 5;9(11):2423. doi: 10.3390/cells9112423.
• [12] Low doses of cisplatin induce gene alterations, cell cycle arrest, and apoptosis in human promyelocytic leukemia cells. Biomark Insights. 2016 Aug 24;11:113-21.
• [13] Effects of 1alpha,25 dihydroxyvitamin D3 and testosterone on miRNA and mRNA expression in LNCaP cells. Mol Cancer. 2011 May 18;10:58.
• [14] Gene expression signatures after ethanol exposure in differentiating embryoid bodies. Toxicol In Vitro. 2018 Feb;46:66-76.
• [15] Lucanthone is a novel inhibitor of autophagy that induces cathepsin D-mediated apoptosis. J Biol Chem. 2011 Feb 25;286(8):6602-13.
• [16] Ethyl carbamate induces cell death through its effects on multiple metabolic pathways. Chem Biol Interact. 2017 Nov 1;277:21-32.
• [17] 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.
• [18] 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.
• [19] Cell-based two-dimensional morphological assessment system to predict cancer drug-induced cardiotoxicity using human induced pluripotent stem cell-derived cardiomyocytes. Toxicol Appl Pharmacol. 2019 Nov 15;383:114761. doi: 10.1016/j.taap.2019.114761. Epub 2019 Sep 15.
• [20] 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.
• [21] 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.