Details of Drug Off-Target (DOT)

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

• DOT Name: Leucine zipper transcription factor-like protein 1 (LZTFL1)
• Gene Name: LZTFL1
• Related Disease:
  Ciliopathy
  Hepatocellular carcinoma
  Lung cancer
  Lung carcinoma
  Bardet-Biedl syndrome 17
  Breast cancer
  Breast carcinoma
  Gastric cancer
  Gonorrhea
  Metastatic malignant neoplasm
  Neoplasm
  Obesity
  Polydactyly
  Stomach cancer
  Bardet biedl syndrome
• UniProt ID: LZTL1_HUMAN
• Pfam ID: PF15294
• Sequence:
  MAELGLNEHHQNEVINYMRFARSKRGLRLKTVDSCFQDLKESRLVEDTFTIDEVSEVLNG
  LQAVVHSEVESELINTAYTNVLLLRQLFAQAEKWYLKLQTDISELENRELLEQVAEFEKA
  EITSSNKKPILDVTKPKLAPLNEGGTAELLNKEILRLQEENEKLKSRLKTIEIQATNALD
  EKSKLEKALQDLQLDQGNQKDFIKAQDLSNLENTVAALKSEFQKTLNDKTENQKSLEENL
  ATAKHDLLRVQEQLHMAEKELEKKFQQTAAYRNMKEILTKKNDQIKDLRKRLAQYEPED
• Function: Regulates ciliary localization of the BBSome complex. Together with the BBSome complex, controls SMO ciliary trafficking and contributes to the sonic hedgehog (SHH) pathway regulation. May play a role in neurite outgrowth. May have tumor suppressor function.
• Tissue Specificity: Expressed in prostate, ovary, stomach, pancreas, esophagus, breast, liver, bladder, kidney, thyroid, colon and lung (at protein level). Down-regulated in multiple primary tumors (at protein level). Detected in testis, heart, skeletal muscle, thymus, spleen, small intestine, and peripheral blood leukocytes.
• Reactome Pathway: BBSome-mediated cargo-targeting to cilium (R-HSA-5620922)

Molecular Interaction Atlas (MIA) of This DOT

15 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Ciliopathy	DIS10G4I	Definitive	Autosomal recessive	[1]
Hepatocellular carcinoma	DIS0J828	Definitive	Biomarker	[2]
Lung cancer	DISCM4YA	Definitive	Biomarker	[2]
Lung carcinoma	DISTR26C	Definitive	Biomarker	[2]
Bardet-Biedl syndrome 17	DISRQV6E	Strong	Autosomal recessive	[3]
Breast cancer	DIS7DPX1	Strong	Altered Expression	[4]
Breast carcinoma	DIS2UE88	Strong	Altered Expression	[4]
Gastric cancer	DISXGOUK	Strong	Biomarker	[5]
Gonorrhea	DISQ5AO6	Strong	Altered Expression	[5]
Metastatic malignant neoplasm	DIS86UK6	Strong	Altered Expression	[6]
Neoplasm	DISZKGEW	Strong	Biomarker	[7]
Obesity	DIS47Y1K	Strong	Biomarker	[8]
Polydactyly	DIS25BMZ	Strong	Biomarker	[3]
Stomach cancer	DISKIJSX	Strong	Biomarker	[5]
Bardet biedl syndrome	DISTBNZW	Supportive	Autosomal recessive	[9]

This DOT Affected the Drug Response of 1 Drug(s)

Drug Name	Drug ID	Highest Status	Interaction	REF
Arsenic trioxide	DM61TA4	Approved	Leucine zipper transcription factor-like protein 1 (LZTFL1) increases the response to substance of Arsenic trioxide.	[26]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Valproate	DMCFE9I	Approved	Valproate decreases the methylation of Leucine zipper transcription factor-like protein 1 (LZTFL1).	[10]
Arsenic	DMTL2Y1	Approved	Arsenic affects the methylation of Leucine zipper transcription factor-like protein 1 (LZTFL1).	[17]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene increases the methylation of Leucine zipper transcription factor-like protein 1 (LZTFL1).	[21]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Ciclosporin	DMAZJFX	Approved	Ciclosporin increases the expression of Leucine zipper transcription factor-like protein 1 (LZTFL1).	[11]
Tretinoin	DM49DUI	Approved	Tretinoin decreases the expression of Leucine zipper transcription factor-like protein 1 (LZTFL1).	[12]
Doxorubicin	DMVP5YE	Approved	Doxorubicin decreases the expression of Leucine zipper transcription factor-like protein 1 (LZTFL1).	[13]
Cupric Sulfate	DMP0NFQ	Approved	Cupric Sulfate decreases the expression of Leucine zipper transcription factor-like protein 1 (LZTFL1).	[14]
Estradiol	DMUNTE3	Approved	Estradiol decreases the expression of Leucine zipper transcription factor-like protein 1 (LZTFL1).	[15]
Ivermectin	DMDBX5F	Approved	Ivermectin decreases the expression of Leucine zipper transcription factor-like protein 1 (LZTFL1).	[16]
Decitabine	DMQL8XJ	Approved	Decitabine decreases the expression of Leucine zipper transcription factor-like protein 1 (LZTFL1).	[18]
Progesterone	DMUY35B	Approved	Progesterone increases the expression of Leucine zipper transcription factor-like protein 1 (LZTFL1).	[19]
Tamibarotene	DM3G74J	Phase 3	Tamibarotene increases the expression of Leucine zipper transcription factor-like protein 1 (LZTFL1).	[20]
PMID28460551-Compound-2	DM4DOUB	Patented	PMID28460551-Compound-2 increases the expression of Leucine zipper transcription factor-like protein 1 (LZTFL1).	[22]
THAPSIGARGIN	DMDMQIE	Preclinical	THAPSIGARGIN increases the expression of Leucine zipper transcription factor-like protein 1 (LZTFL1).	[23]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A increases the expression of Leucine zipper transcription factor-like protein 1 (LZTFL1).	[24]
geraniol	DMS3CBD	Investigative	geraniol increases the expression of Leucine zipper transcription factor-like protein 1 (LZTFL1).	[25]

References

• [1] Technical standards for the interpretation and reporting of constitutional copy-number variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics (ACMG) and the Clinical Genome Resource (ClinGen). Genet Med. 2020 Feb;22(2):245-257. doi: 10.1038/s41436-019-0686-8. Epub 2019 Nov 6.
• [2] Tumor suppressive functions of LZTFL1 in hepatocellular carcinoma.Onco Targets Ther. 2019 Jul 10;12:5537-5544. doi: 10.2147/OTT.S196925. eCollection 2019.
• [3] Mesoaxial polydactyly is a major feature in Bardet-Biedl syndrome patients with LZTFL1 (BBS17) mutations. Clin Genet. 2014 May;85(5):476-81. doi: 10.1111/cge.12198. Epub 2013 Jun 12.
• [4] microRNA-21 promotes breast cancer proliferation and metastasis by targeting LZTFL1.BMC Cancer. 2019 Jul 27;19(1):738. doi: 10.1186/s12885-019-5951-3.
• [5] LZTFL1 suppresses gastric cancer cell migration and invasion through regulating nuclear translocation of -catenin.J Cancer Res Clin Oncol. 2014 Dec;140(12):1997-2008. doi: 10.1007/s00432-014-1753-9. Epub 2014 Jul 9.
• [6] Tumor-suppressive functions of leucine zipper transcription factor-like 1.Cancer Res. 2010 Apr 1;70(7):2942-50. doi: 10.1158/0008-5472.CAN-09-3826. Epub 2010 Mar 16.
• [7] Combinations of Tyrosine Kinase Inhibitor and ERAD Inhibitor Promote Oxidative Stress-Induced Apoptosis through ATF4 and KLF9 in Medullary Thyroid Cancer.Mol Cancer Res. 2019 Mar;17(3):751-760. doi: 10.1158/1541-7786.MCR-18-0354. Epub 2018 Dec 14.
• [8] Molecular Characterization and Functional Analysis of Leucine Zipper Transcription Factor Like 1 in Zebrafish (Danio rerio).Front Physiol. 2019 Jun 25;10:801. doi: 10.3389/fphys.2019.00801. eCollection 2019.
• [9] Exome sequencing identifies mutations in LZTFL1, a BBSome and smoothened trafficking regulator, in a family with Bardet--Biedl syndrome with situs inversus and insertional polydactyly. J Med Genet. 2012 May;49(5):317-21. doi: 10.1136/jmedgenet-2012-100737. Epub 2012 Apr 17.
• [10] 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.
• [11] Comparison of HepG2 and HepaRG by whole-genome gene expression analysis for the purpose of chemical hazard identification. Toxicol Sci. 2010 May;115(1):66-79.
• [12] 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.
• [13] Bringing in vitro analysis closer to in vivo: studying doxorubicin toxicity and associated mechanisms in 3D human microtissues with PBPK-based dose modelling. Toxicol Lett. 2018 Sep 15;294:184-192.
• [14] Physiological and toxicological transcriptome changes in HepG2 cells exposed to copper. Physiol Genomics. 2009 Aug 7;38(3):386-401.
• [15] 17-Estradiol Activates HSF1 via MAPK Signaling in ER-Positive Breast Cancer Cells. Cancers (Basel). 2019 Oct 11;11(10):1533. doi: 10.3390/cancers11101533.
• [16] 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.
• [17] 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.
• [18] DNA methylation inhibits p53-mediated survivin repression. Oncogene. 2009 May 14;28(19):2046-50. doi: 10.1038/onc.2009.62. Epub 2009 Apr 13.
• [19] Progesterone promotes differentiation of human cord blood fetal T cells into T regulatory cells but suppresses their differentiation into Th17 cells. J Immunol. 2011 Aug 15;187(4):1778-87. doi: 10.4049/jimmunol.1003919. Epub 2011 Jul 18.
• [20] Induction of class II major histocompatibility complex expression in human multiple myeloma cells by retinoid. Haematologica. 2007 Jan;92(1):115-20.
• [21] 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.
• [22] 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.
• [23] Endoplasmic reticulum stress impairs insulin signaling through mitochondrial damage in SH-SY5Y cells. Neurosignals. 2012;20(4):265-80.
• [24] Identification of mechanisms of action of bisphenol a-induced human preadipocyte differentiation by transcriptional profiling. Obesity (Silver Spring). 2014 Nov;22(11):2333-43.
• [25] Geraniol suppresses prostate cancer growth through down-regulation of E2F8. Cancer Med. 2016 Oct;5(10):2899-2908.
• [26] The NRF2-mediated oxidative stress response pathway is associated with tumor cell resistance to arsenic trioxide across the NCI-60 panel. BMC Med Genomics. 2010 Aug 13;3:37. doi: 10.1186/1755-8794-3-37.