Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTXXL864)

• DOT Name: Leucine zipper putative tumor suppressor 1 (LZTS1)
• Synonyms: F37/esophageal cancer-related gene-coding leucine-zipper motif; Fez1
• Gene Name: LZTS1
• Related Disease:
  Bladder cancer
  Prostate carcinoma
  Urinary bladder cancer
  Urinary bladder neoplasm
  Advanced cancer
  Breast cancer
  Breast carcinoma
  Colorectal carcinoma
  Esophageal squamous cell carcinoma
  Familial prostate carcinoma
  Hepatocellular carcinoma
  Hereditary chronic pancreatitis
  Kidney cancer
  Lung carcinoma
  Melanoma
  Neoplasm
  Neoplasm of esophagus
  Prostate cancer
  Renal carcinoma
  Stomach cancer
  Tarsal-carpal coalition syndrome
  Transitional cell carcinoma
  Triple negative breast cancer
  Adenocarcinoma
  Bone osteosarcoma
  Epithelial ovarian cancer
  Lung cancer
  Osteosarcoma
  Ovarian cancer
  Ovarian neoplasm
  Carcinoma
  Cutaneous squamous cell carcinoma
  Prostate neoplasm
  Squamous cell carcinoma
• UniProt ID: LZTS1_HUMAN
• Pfam ID: PF06818
• Sequence:
  MGSVSSLISGHSFHSKHCRASQYKLRKSSHLKKLNRYSDGLLRFGFSQDSGHGKSSSKMG
  KSEDFFYIKVSQKARGSHHPDYTALSSGDLGGQAGVDFDPSTPPKLMPFSNQLEMGSEKG
  AVRPTAFKPVLPRSGAILHSSPESASHQLHPAPPDKPKEQELKPGLCSGALSDSGRNSMS
  SLPTHSTSSSYQLDPLVTPVGPTSRFGGSAHNITQGIVLQDSNMMSLKALSFSDGGSKLG
  HSNKADKGPSCVRSPISTDECSIQELEQKLLEREGALQKLQRSFEEKELASSLAYEERPR
  RCRDELEGPEPKGGNKLKQASQKSQRAQQVLHLQVLQLQQEKRQLRQELESLMKEQDLLE
  TKLRSYEREKTSFGPALEETQWEVCQKSGEISLLKQQLKESQTEVNAKASEILGLKAQLK
  DTRGKLEGLELRTQDLEGALRTKGLELEVCENELQRKKNEAELLREKVNLLEQELQELRA
  QAALARDMGPPTFPEDVPALQRELERLRAELREERQGHDQMSSGFQHERLVWKEEKEKVI
  QYQKQLQQSYVAMYQRNQRLEKALQQLARGDSAGEPLEVDLEGADIPYEDIIATEI
• Function: Involved in the regulation of cell growth. May stabilize the active CDC2-cyclin B1 complex and thereby contribute to the regulation of the cell cycle and the prevention of uncontrolled cell proliferation. May act as a tumor suppressor.
• Tissue Specificity: Highly expressed in testis, prostate, spleen, thymus, ovary and brain. Detected at lower levels in heart, placenta, small intestine, colon, liver, kidney, skeletal muscle and pancreas. Not detectable in primary tumors from breast and prostate and in many cancer cell lines.

Molecular Interaction Atlas (MIA) of This DOT

34 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Bladder cancer	DISUHNM0	Definitive	Biomarker	[1]
Prostate carcinoma	DISMJPLE	Definitive	Biomarker	[2]
Urinary bladder cancer	DISDV4T7	Definitive	Biomarker	[1]
Urinary bladder neoplasm	DIS7HACE	Definitive	Biomarker	[1]
Advanced cancer	DISAT1Z9	Strong	Altered Expression	[3]
Breast cancer	DIS7DPX1	Strong	Biomarker	[4]
Breast carcinoma	DIS2UE88	Strong	Biomarker	[4]
Colorectal carcinoma	DIS5PYL0	Strong	Biomarker	[5]
Esophageal squamous cell carcinoma	DIS5N2GV	Strong	Biomarker	[6]
Familial prostate carcinoma	DISL9KNO	Strong	Biomarker	[7]
Hepatocellular carcinoma	DIS0J828	Strong	Biomarker	[8]
Hereditary chronic pancreatitis	DISF0J1Q	Strong	Biomarker	[7]
Kidney cancer	DISBIPKM	Strong	Biomarker	[9]
Lung carcinoma	DISTR26C	Strong	Biomarker	[10]
Melanoma	DIS1RRCY	Strong	Altered Expression	[11]
Neoplasm	DISZKGEW	Strong	Biomarker	[5]
Neoplasm of esophagus	DISOLKAQ	Strong	Genetic Variation	[7]
Prostate cancer	DISF190Y	Strong	Biomarker	[2]
Renal carcinoma	DISER9XT	Strong	Biomarker	[9]
Stomach cancer	DISKIJSX	Strong	Genetic Variation	[12]
Tarsal-carpal coalition syndrome	DISY90L2	Strong	Biomarker	[13]
Transitional cell carcinoma	DISWVVDR	Strong	Altered Expression	[13]
Triple negative breast cancer	DISAMG6N	Strong	Altered Expression	[14]
Adenocarcinoma	DIS3IHTY	moderate	Genetic Variation	[15]
Bone osteosarcoma	DIST1004	moderate	Altered Expression	[16]
Epithelial ovarian cancer	DIS56MH2	moderate	Biomarker	[15]
Lung cancer	DISCM4YA	moderate	Biomarker	[10]
Osteosarcoma	DISLQ7E2	moderate	Altered Expression	[16]
Ovarian cancer	DISZJHAP	moderate	Biomarker	[15]
Ovarian neoplasm	DISEAFTY	moderate	Biomarker	[15]
Carcinoma	DISH9F1N	Limited	Biomarker	[17]
Cutaneous squamous cell carcinoma	DIS3LXUG	Limited	Altered Expression	[3]
Prostate neoplasm	DISHDKGQ	Limited	Genetic Variation	[7]
Squamous cell carcinoma	DISQVIFL	Limited	Altered Expression	[18]

2 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 Leucine zipper putative tumor suppressor 1 (LZTS1).	[19]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene increases the methylation of Leucine zipper putative tumor suppressor 1 (LZTS1).	[29]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Tretinoin	DM49DUI	Approved	Tretinoin decreases the expression of Leucine zipper putative tumor suppressor 1 (LZTS1).	[20]
Cisplatin	DMRHGI9	Approved	Cisplatin affects the expression of Leucine zipper putative tumor suppressor 1 (LZTS1).	[21]
Ivermectin	DMDBX5F	Approved	Ivermectin decreases the expression of Leucine zipper putative tumor suppressor 1 (LZTS1).	[22]
Temozolomide	DMKECZD	Approved	Temozolomide increases the expression of Leucine zipper putative tumor suppressor 1 (LZTS1).	[23]
Calcitriol	DM8ZVJ7	Approved	Calcitriol increases the expression of Leucine zipper putative tumor suppressor 1 (LZTS1).	[24]
Vorinostat	DMWMPD4	Approved	Vorinostat decreases the expression of Leucine zipper putative tumor suppressor 1 (LZTS1).	[25]
Decitabine	DMQL8XJ	Approved	Decitabine affects the expression of Leucine zipper putative tumor suppressor 1 (LZTS1).	[21]
Zoledronate	DMIXC7G	Approved	Zoledronate decreases the expression of Leucine zipper putative tumor suppressor 1 (LZTS1).	[26]
Panobinostat	DM58WKG	Approved	Panobinostat increases the expression of Leucine zipper putative tumor suppressor 1 (LZTS1).	[27]
Malathion	DMXZ84M	Approved	Malathion increases the expression of Leucine zipper putative tumor suppressor 1 (LZTS1).	[28]
SNDX-275	DMH7W9X	Phase 3	SNDX-275 increases the expression of Leucine zipper putative tumor suppressor 1 (LZTS1).	[27]
PMID28460551-Compound-2	DM4DOUB	Patented	PMID28460551-Compound-2 decreases the expression of Leucine zipper putative tumor suppressor 1 (LZTS1).	[30]
UNC0379	DMD1E4J	Preclinical	UNC0379 decreases the expression of Leucine zipper putative tumor suppressor 1 (LZTS1).	[31]
Trichostatin A	DM9C8NX	Investigative	Trichostatin A increases the expression of Leucine zipper putative tumor suppressor 1 (LZTS1).	[32]
Acetaldehyde	DMJFKG4	Investigative	Acetaldehyde increases the expression of Leucine zipper putative tumor suppressor 1 (LZTS1).	[33]

References

• [1] Mutation analysis of the 8p candidate tumour suppressor genes DBC2 (RHOBTB2) and LZTS1 in bladder cancer.Cancer Lett. 2005 Jul 8;225(1):121-30. doi: 10.1016/j.canlet.2004.10.047. Epub 2004 Dec 10.
• [2] Targeting CDC25C, PLK1 and CHEK1 to overcome Docetaxel resistance induced by loss of LZTS1 in prostate cancer.Oncotarget. 2014 Feb 15;5(3):667-78. doi: 10.18632/oncotarget.1574.
• [3] MicroRNA-135b Regulates Leucine Zipper Tumor Suppressor 1 in Cutaneous Squamous Cell Carcinoma.PLoS One. 2015 May 4;10(5):e0125412. doi: 10.1371/journal.pone.0125412. eCollection 2015.
• [4] LZTS1 downregulation confers paclitaxel resistance and is associated with worse prognosis in breast cancer.Oncotarget. 2014 Feb 28;5(4):970-7. doi: 10.18632/oncotarget.1630.
• [5] The tumor-suppressor gene LZTS1 suppresses colorectal cancer proliferation through inhibition of the AKT-mTOR signaling pathway.Cancer Lett. 2015 Apr 28;360(1):68-75. doi: 10.1016/j.canlet.2015.02.004. Epub 2015 Feb 7.
• [6] MiR-214 promotes cell meastasis and inhibites apoptosis of esophageal squamous cell carcinoma via PI3K/AKT/mTOR signaling pathway.Biomed Pharmacother. 2018 Sep;105:350-361. doi: 10.1016/j.biopha.2018.05.149. Epub 2018 Jun 1.
• [7] Germline sequence variants of the LZTS1 gene are associated with prostate cancer risk.Cancer Genet Cytogenet. 2002 Aug;137(1):1-7. doi: 10.1016/s0165-4608(02)00549-6.
• [8] The tumor-suppressor gene LZTS1 suppresses hepatocellular carcinoma proliferation by impairing PI3K/Akt pathway.Biomed Pharmacother. 2015 Dec;76:141-6. doi: 10.1016/j.biopha.2015.10.006. Epub 2015 Nov 18.
• [9] Collecting duct carcinoma of the kidney: an immunohistochemical study of 11 cases.BMC Urol. 2004 Sep 9;4:11. doi: 10.1186/1471-2490-4-11.
• [10] MicroRNA-135b promotes lung cancer metastasis by regulating multiple targets in the Hippo pathway and LZTS1.Nat Commun. 2013;4:1877. doi: 10.1038/ncomms2876.
• [11] A metastasis modifier locus on human chromosome 8p in uveal melanoma identified by integrative genomic analysis.Clin Cancer Res. 2008 Jun 15;14(12):3737-45. doi: 10.1158/1078-0432.CCR-07-5144.
• [12] Fez1/lzts1 alterations in gastric carcinoma.Clin Cancer Res. 2001 Jun;7(6):1546-52.
• [13] FEZ1/LZTS1 is down-regulated in high-grade bladder cancer, and its restoration suppresses tumorigenicity in transitional cell carcinoma cells.Am J Pathol. 2002 Apr;160(4):1345-52. doi: 10.1016/S0002-9440(10)62561-8.
• [14] miR-1207-5p regulates the sensitivity of triple-negative breast cancer cells to Taxol treatment via the suppression of LZTS1 expression.Oncol Lett. 2019 Jan;17(1):990-998. doi: 10.3892/ol.2018.9687. Epub 2018 Nov 12.
• [15] Mutation and expression analysis of LZTS1 in ovarian cancer.Cancer Lett. 2006 Feb 20;233(1):151-7. doi: 10.1016/j.canlet.2005.03.008.
• [16] miR-214 promotes the proliferation and invasion of osteosarcoma cells through direct suppression of LZTS1.Biochem Biophys Res Commun. 2014 Jun 27;449(2):190-5. doi: 10.1016/j.bbrc.2014.04.140. Epub 2014 May 4.
• [17] Functional identification of LZTS1 as a candidate prostate tumor suppressor gene on human chromosome 8p22.Oncogene. 2001 Jul 12;20(31):4169-79. doi: 10.1038/sj.onc.1204539.
• [18] Down-regulation of FEZ1/LZTS1 gene with frequent loss of heterozygosity in oral squamous cell carcinomas.Int J Oncol. 2003 Aug;23(2):297-302.
• [19] 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.
• [20] 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.
• [21] Acute hypersensitivity of pluripotent testicular cancer-derived embryonal carcinoma to low-dose 5-aza deoxycytidine is associated with global DNA Damage-associated p53 activation, anti-pluripotency and DNA demethylation. PLoS One. 2012;7(12):e53003. doi: 10.1371/journal.pone.0053003. Epub 2012 Dec 27.
• [22] 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.
• [23] Temozolomide induces activation of Wnt/-catenin signaling in glioma cells via PI3K/Akt pathway: implications in glioma therapy. Cell Biol Toxicol. 2020 Jun;36(3):273-278. doi: 10.1007/s10565-019-09502-7. Epub 2019 Nov 22.
• [24] Large-scale in silico and microarray-based identification of direct 1,25-dihydroxyvitamin D3 target genes. Mol Endocrinol. 2005 Nov;19(11):2685-95.
• [25] Definition of transcriptome-based indices for quantitative characterization of chemically disturbed stem cell development: introduction of the STOP-Toxukn and STOP-Toxukk tests. Arch Toxicol. 2017 Feb;91(2):839-864.
• [26] Interleukin-19 as a translational indicator of renal injury. Arch Toxicol. 2015 Jan;89(1):101-6.
• [27] 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.
• [28] Exposure to Insecticides Modifies Gene Expression and DNA Methylation in Hematopoietic Tissues In Vitro. Int J Mol Sci. 2023 Mar 26;24(7):6259. doi: 10.3390/ijms24076259.
• [29] 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.
• [30] 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.
• [31] Epigenetic siRNA and chemical screens identify SETD8 inhibition as a therapeutic strategy for p53 activation in high-risk neuroblastoma. Cancer Cell. 2017 Jan 9;31(1):50-63.
• [32] From transient transcriptome responses to disturbed neurodevelopment: role of histone acetylation and methylation as epigenetic switch between reversible and irreversible drug effects. Arch Toxicol. 2014 Jul;88(7):1451-68.
• [33] Transcriptome profile analysis of saturated aliphatic aldehydes reveals carbon number-specific molecules involved in pulmonary toxicity. Chem Res Toxicol. 2014 Aug 18;27(8):1362-70.