Details of Drug Off-Target (DOT)

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

• DOT Name: Lethal(2) giant larvae protein homolog 1 (LLGL1)
• Synonyms: LLGL; DLG4; Hugl-1; Human homolog to the D-lgl gene protein
• Gene Name: LLGL1
• Related Disease:
  Acute monocytic leukemia
  Acute myelogenous leukaemia
  Advanced cancer
  Autosomal dominant epilepsy with auditory features
  Breast cancer
  Breast carcinoma
  Breast neoplasm
  Bronchopulmonary dysplasia
  Carcinoma of esophagus
  Colon cancer
  Colon carcinoma
  Congenital diaphragmatic hernia
  Endometrial cancer
  Endometrial carcinoma
  Endometrium neoplasm
  Epilepsy, familial temporal lobe, 1
  Esophageal cancer
  Esophageal squamous cell carcinoma
  Glioma
  Hepatocellular carcinoma
  leukaemia
  Leukemia
  Malignant glioma
  Neoplasm of esophagus
  Non-small-cell lung cancer
  Pancreatic adenocarcinoma
  Pancreatic cancer
  Periventricular nodular heterotopia
  Smith-Magenis syndrome
  Melanoma
  Subcortical band heterotopia
  Colorectal carcinoma
  Colorectal neoplasm
  Nervous system inflammation
  Tourette syndrome
• UniProt ID: L2GL1_HUMAN
• Pfam ID: PF08366
• Sequence:
  MMKFRFRRQGADPQREKLKQELFAFNKTVEHGFPNQPSALAFDPELRIMAIGTRSGAVKI
  YGAPGVEFTGLHRDAATVTQMHFLTGQGRLLSLLDDSSLHLWEIVHHNGCAHLEEALSFQ
  LPSRPGFDGASAPLSLTRVTVVLLVAASDIAALGTEGSSVFFLDVTTLTLLEGQTLAPGE
  VLRSVPDDYRCGKALGPVESLQGHLRDPTKILIGYSRGLLVIWNQASQCVDHIFLGNQQL
  ESLCWGRDSSTVVSSHSDGSYAVWSVDAGSFPTLQPTVATTPYGPFPCKAINKILWRNCE
  SGGHFIIFSGGMPRASYGDRHCVSVLRAETLVTLDFTSRIIDFFTVHSTRPEDEFDDPQA
  LAVLLEEELVVLDLQTPGWPAVPAPYLAPLHSSAITCSAHVASVPAKLWARIVSAGEQQS
  PQPVSSALSWPITGGRNLAQEPSQRGLLLTGHEDGTVRFWDASGVALRPLYKLSTAGLFQ
  TDCEHADSLAQAAEDDWPPFRKVGCFDPYSDDPRLGVQKVALCKYTAQMVVAGTAGQVLV
  LELSDVPVEQAVSVAIIDLLQDREGFTWKGHERLSPRTGPLPWPAGFQPRVLVQCLPPAA
  VTAVTLHTEWSLVAFGTSHGFGLFDYQRKSPVLARCTLHPNDSLAMEGPLSRVKSLKKSL
  RQSFRRIRKSRVSGKKRAANASSKLQEANAQLAEQACPHDVEMTPVQRRIEPRSADDSLS
  GVVRCLYFADTFLRDGAHHGPTMWAGTNSGSVFAYALEVPAAAVGGEKRPEQAVEAVLGK
  EVQLMHRAPVVAIAVLDGRGRPLPEPYEASRDLAQAPDMQGGHAVLIASEEQFKVFTLPK
  VSAKTKFKLTAHEGCRVRKVALATFASVACEDYAETCLACLTNLGDVHVFSVPGLRPQVH
  YSCIRKEDISGIASCVFTRHGQGFYLISPSEFERFSLSARNITEPLCSLDINWPRDATQA
  SYRIRESPKLSQANGTPSILLAPQSLDGSPDPAHSMGPDTPEPPEAALSPMSIDSATSAD
  TTLDTTGDVTVEDVKDFLGSSEESEKNLRNLAEDEAHACAILIK
• Function: Cortical cytoskeleton protein found in a complex involved in maintaining cell polarity and epithelial integrity. Involved in the regulation of mitotic spindle orientation, proliferation, differentiation and tissue organization of neuroepithelial cells. Involved in axonogenesis through RAB10 activation thereby regulating vesicular membrane trafficking toward the axonal plasma membrane.
• Tissue Specificity: Expressed in brain, kidney, and muscle but is barely seen in heart and placenta. Down-regulated or lost in all cell lines and in most of the tumor samples analyzed. Loss was associated with advanced stage of the disease.
• KEGG Pathway:
  Hippo sig.ling pathway (hsa04390)
  Tight junction (hsa04530)
  Human papillomavirus infection (hsa05165)

Molecular Interaction Atlas (MIA) of This DOT

35 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Acute monocytic leukemia	DIS28NEL	Strong	Biomarker	[1]
Acute myelogenous leukaemia	DISCSPTN	Strong	Altered Expression	[1]
Advanced cancer	DISAT1Z9	Strong	Biomarker	[2]
Autosomal dominant epilepsy with auditory features	DISFZN2O	Strong	Genetic Variation	[3]
Breast cancer	DIS7DPX1	Strong	Biomarker	[4]
Breast carcinoma	DIS2UE88	Strong	Biomarker	[4]
Breast neoplasm	DISNGJLM	Strong	Biomarker	[4]
Bronchopulmonary dysplasia	DISO0BY5	Strong	Biomarker	[5]
Carcinoma of esophagus	DISS6G4D	Strong	Biomarker	[6]
Colon cancer	DISVC52G	Strong	Biomarker	[7]
Colon carcinoma	DISJYKUO	Strong	Biomarker	[7]
Congenital diaphragmatic hernia	DIS0IPVU	Strong	Altered Expression	[8]
Endometrial cancer	DISW0LMR	Strong	Altered Expression	[7]
Endometrial carcinoma	DISXR5CY	Strong	Altered Expression	[7]
Endometrium neoplasm	DIS6OS2L	Strong	Altered Expression	[7]
Epilepsy, familial temporal lobe, 1	DISTRYUX	Strong	Genetic Variation	[3]
Esophageal cancer	DISGB2VN	Strong	Biomarker	[6]
Esophageal squamous cell carcinoma	DIS5N2GV	Strong	Biomarker	[6]
Glioma	DIS5RPEH	Strong	Biomarker	[9]
Hepatocellular carcinoma	DIS0J828	Strong	Biomarker	[10]
leukaemia	DISS7D1V	Strong	Biomarker	[1]
Leukemia	DISNAKFL	Strong	Biomarker	[1]
Malignant glioma	DISFXKOV	Strong	Biomarker	[9]
Neoplasm of esophagus	DISOLKAQ	Strong	Biomarker	[6]
Non-small-cell lung cancer	DIS5Y6R9	Strong	Altered Expression	[11]
Pancreatic adenocarcinoma	DISKHX7S	Strong	Altered Expression	[12]
Pancreatic cancer	DISJC981	Strong	Altered Expression	[12]
Periventricular nodular heterotopia	DISU3ZRI	Strong	Biomarker	[13]
Smith-Magenis syndrome	DISG4G6X	Strong	Biomarker	[14]
Melanoma	DIS1RRCY	moderate	Biomarker	[7]
Subcortical band heterotopia	DISHN7JS	moderate	Biomarker	[15]
Colorectal carcinoma	DIS5PYL0	Limited	Altered Expression	[16]
Colorectal neoplasm	DISR1UCN	Limited	Altered Expression	[16]
Nervous system inflammation	DISB3X5A	Limited	Biomarker	[17]
Tourette syndrome	DISX9D54	No Known	Unknown	[18]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Valproate	DMCFE9I	Approved	Valproate affects the expression of Lethal(2) giant larvae protein homolog 1 (LLGL1).	[19]
Tretinoin	DM49DUI	Approved	Tretinoin decreases the expression of Lethal(2) giant larvae protein homolog 1 (LLGL1).	[20]
Ivermectin	DMDBX5F	Approved	Ivermectin decreases the expression of Lethal(2) giant larvae protein homolog 1 (LLGL1).	[21]
Tacrolimus	DMZ7XNQ	Approved	Tacrolimus increases the expression of Lethal(2) giant larvae protein homolog 1 (LLGL1).	[22]
PMID28460551-Compound-2	DM4DOUB	Patented	PMID28460551-Compound-2 increases the expression of Lethal(2) giant larvae protein homolog 1 (LLGL1).	[23]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A decreases the expression of Lethal(2) giant larvae protein homolog 1 (LLGL1).	[24]
Trichostatin A	DM9C8NX	Investigative	Trichostatin A decreases the expression of Lethal(2) giant larvae protein homolog 1 (LLGL1).	[25]
Milchsaure	DM462BT	Investigative	Milchsaure decreases the expression of Lethal(2) giant larvae protein homolog 1 (LLGL1).	[26]

References

• [1] The cell fate determinant Llgl1 influences HSC fitness and prognosis in AML.J Exp Med. 2013 Jan 14;210(1):15-22. doi: 10.1084/jem.20120596. Epub 2012 Dec 31.
• [2] LLGL2 rescues nutrient stress by promoting leucine uptake in ER(+) breast cancer.Nature. 2019 May;569(7755):275-279. doi: 10.1038/s41586-019-1126-2. Epub 2019 Apr 17.
• [3] Molecular basis of Mendelian idiopathic epilepsies.Ann Med. 2004;36(2):89-97. doi: 10.1080/07853890310019952.
• [4] ERE-independent ERalpha target genes differentially expressed in human breast tumors. Mol Cell Endocrinol. 2005 Dec 21;245(1-2):53-9. doi: 10.1016/j.mce.2005.10.003. Epub 2005 Nov 17.
• [5] LGL1 modulates proliferation, apoptosis, and migration of human fetal lung fibroblasts.Am J Physiol Lung Cell Mol Physiol. 2015 Feb 15;308(4):L391-402. doi: 10.1152/ajplung.00119.2014. Epub 2014 Dec 5.
• [6] Hugl-1 induces apoptosis in esophageal carcinoma cells both in vitro and in vivo.World J Gastroenterol. 2013 Jul 14;19(26):4127-36. doi: 10.3748/wjg.v19.i26.4127.
• [7] Loss of Hugl-1 expression associates with lymph node metastasis in endometrial cancer.Oncol Res. 2007;16(9):431-5. doi: 10.3727/000000007783980855.
• [8] The effects of tracheal occlusion on Wnt signaling in a rabbit model of congenital diaphragmatic hernia.J Pediatr Surg. 2019 May;54(5):937-944. doi: 10.1016/j.jpedsurg.2019.01.024. Epub 2019 Jan 31.
• [9] Hugl-1 inhibits glioma cell growth in intracranial model.J Neurooncol. 2015 Oct;125(1):113-21. doi: 10.1007/s11060-015-1901-3. Epub 2015 Sep 4.
• [10] Aberrant splicing of Hugl-1 is associated with hepatocellular carcinoma progression.Clin Cancer Res. 2009 May 15;15(10):3287-96. doi: 10.1158/1078-0432.CCR-08-2078. Epub 2009 May 15.
• [11] MiR-652-3p is upregulated in non-small cell lung cancer and promotes proliferation and metastasis by directly targeting Lgl1.Oncotarget. 2016 Mar 29;7(13):16703-15. doi: 10.18632/oncotarget.7697.
• [12] Preservation of HUGL-1 expression as a favourable prognostic factor in pancreatic carcinoma.Anticancer Res. 2012 Aug;32(8):3153-9.
• [13] Llgl1 Connects Cell Polarity with Cell-Cell Adhesion in Embryonic Neural Stem Cells.Dev Cell. 2017 Jun 5;41(5):481-495.e5. doi: 10.1016/j.devcel.2017.05.002. Epub 2017 May 25.
• [14] The brain finger protein gene (ZNF179), a member of the RING finger family, maps within the Smith-Magenis syndrome region at 17p11.2.Am J Med Genet. 1997 Mar 31;69(3):320-4.
• [15] Loss of Lgl1 Disrupts the Radial Glial Fiber-guided Cortical Neuronal Migration and Causes Subcortical Band Heterotopia in Mice.Neuroscience. 2019 Feb 21;400:132-145. doi: 10.1016/j.neuroscience.2018.12.039. Epub 2018 Dec 28.
• [16] Reduced expression of Hugl-1, the human homologue of Drosophila tumour suppressor gene lgl, contributes to progression of colorectal cancer.Oncogene. 2005 Apr 28;24(19):3100-9. doi: 10.1038/sj.onc.1208520.
• [17] Macrophage galactose-type lectin (MGL) is induced on M2 microglia and participates in the resolution phase of autoimmune neuroinflammation.J Neuroinflammation. 2019 Jun 27;16(1):130. doi: 10.1186/s12974-019-1522-4.
• [18] De Novo Coding Variants Are Strongly Associated with Tourette Disorder. Neuron. 2017 May 3;94(3):486-499.e9. doi: 10.1016/j.neuron.2017.04.024.
• [19] Gene Expression Regulation and Pathway Analysis After Valproic Acid and Carbamazepine Exposure in a Human Embryonic Stem Cell-Based Neurodevelopmental Toxicity Assay. Toxicol Sci. 2015 Aug;146(2):311-20. doi: 10.1093/toxsci/kfv094. Epub 2015 May 15.
• [20] 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.
• [21] 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.
• [22] Calcineurin is an important factor involved in glucose uptake in human adipocytes. Mol Cell Biochem. 2018 Aug;445(1-2):157-168. doi: 10.1007/s11010-017-3261-0. Epub 2018 Jan 27.
• [23] 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.
• [24] Isobaric tags for relative and absolute quantitation-based proteomics analysis of the effect of ginger oil on bisphenol A-induced breast cancer cell proliferation. Oncol Lett. 2021 Feb;21(2):101. doi: 10.3892/ol.2020.12362. Epub 2020 Dec 8.
• [25] A transcriptome-based classifier to identify developmental toxicants by stem cell testing: design, validation and optimization for histone deacetylase inhibitors. Arch Toxicol. 2015 Sep;89(9):1599-618.
• [26] Transcriptional profiling of lactic acid treated reconstructed human epidermis reveals pathways underlying stinging and itch. Toxicol In Vitro. 2019 Jun;57:164-173.