Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTS6CHG2)

• DOT Name: Band 4.1-like protein 3 (EPB41L3)
• Synonyms: 4.1B; Differentially expressed in adenocarcinoma of the lung protein 1; DAL-1; Erythrocyte membrane protein band 4.1-like 3
• Gene Name: EPB41L3
• Related Disease:
  Adenocarcinoma
  Ependymoma
  Lung cancer
  Lung carcinoma
  Meningioma
  Neurofibromatosis type 2
  Squamous cell carcinoma
  Advanced cancer
  Brain neoplasm
  Breast cancer
  Breast carcinoma
  Cervical Intraepithelial neoplasia
  Clear cell renal carcinoma
  Cryptococcosis
  Dysplasia of cervix
  Esophageal squamous cell carcinoma
  Lung neoplasm
  Metastatic malignant neoplasm
  Neoplasm
  Oropharyngeal cancer
  Oropharyngeal carcinoma
  Prostate cancer
  Prostate carcinoma
  Prostate neoplasm
  Schizophrenia
  Small-cell lung cancer
  T-cell lymphoma
  Carcinoma
  Hepatocellular carcinoma
  Lung adenocarcinoma
  Breast neoplasm
  Epithelial ovarian cancer
  Gastric cancer
  Non-small-cell lung cancer
  Ovarian cancer
  Ovarian neoplasm
  Stomach cancer
• UniProt ID: E41L3_HUMAN
• PDB ID: 2HE7 ; 3BIN ; 5RYM ; 5RYN ; 5RYO ; 5RYP ; 5RYQ ; 5RYR ; 5RYS ; 5RYT ; 5RYU ; 5RYV ; 5RYW ; 5RYX ; 5RYY ; 5RYZ ; 5RZ0 ; 5RZ1 ; 5RZ2 ; 5RZ3 ; 5RZ4 ; 5RZ5 ; 5RZ6 ; 5RZ7 ; 5RZ8 ; 5RZ9 ; 5RZA ; 5RZB ; 5RZC ; 5RZD ; 5RZE ; 5RZF ; 5RZG ; 5RZH ; 5RZI ; 5RZJ ; 5RZK ; 5RZL ; 5RZM ; 5RZN ; 5RZO ; 5RZP ; 5RZQ ; 5RZR ; 5RZS ; 5RZT ; 5RZU ; 5RZV ; 5RZW ; 5RZX ; 5RZY ; 5RZZ ; 5S00 ; 6IBE
• Pfam ID: PF05902 ; PF08736 ; PF09380 ; PF00373 ; PF09379 ; PF04382
• Sequence:
  MTTESGSDSESKPDQEAEPQEAAGAQGRAGAPVPEPPKEEQQQALEQFAAAAAHSTPVRR
  EVTDKEQEFAARAAKQLEYQQLEDDKLSQKSSSSKLSRSPLKIVKKPKSMQCKVILLDGS
  EYTCDVEKRSRGQVLFDKVCEHLNLLEKDYFGLTYRDAENQKNWLDPAKEIKKQVRSGAW
  HFSFNVKFYPPDPAQLSEDITRYYLCLQLRDDIVSGRLPCSFVTLALLGSYTVQSELGDY
  DPDECGSDYISEFRFAPNHTKELEDKVIELHKSHRGMTPAEAEMHFLENAKKLSMYGVDL
  HHAKDSEGVEIMLGVCASGLLIYRDRLRINRFAWPKVLKISYKRNNFYIKIRPGEFEQFE
  STIGFKLPNHRAAKRLWKVCVEHHTFFRLLLPEAPPKKFLTLGSKFRYSGRTQAQTRRAS
  ALIDRPAPYFERSSSKRYTMSRSLDGEVGTGQYATTKGISQTNLITTVTPEKKAEEERDE
  EEDKRRKGEEVTPISAIRHEGKSPGLGTDSCPLSPPSTHCAPTSPTELRRRCKENDCKLP
  GYEPSRAEHLPGEPALDSDGPGRPYLGDQDVAFSYRQQTGKGTTLFSFSLQLPESFPSLL
  DDDGYLSFPNLSETNLLPQSLQHYLPIRSPSLVPCFLFIFFFLLSASFSVPYALTLSFPL
  ALCLCYLEPKAASLSASLDNDPSDSSEEETDSERTDTAADGETTATESDQEEDAELKAQE
  LEKTQDDLMKHQTNISELKRTFLETSTDTAVTNEWEKRLSTSPVRLAARQEDAPMIEPLV
  PEETKQSSGEKLMDGSEIFSLLESARKPTEFIGGVTSTSQSWVQKMETKTESSGIETEPT
  VHHLPLSTEKVVQETVLVEERRVVHASGDASYSAGDSGDAAAQPAFTGIKGKEGSALTEG
  AKEEGGEEVAKAVLEQEETAAASRERQEEQSAAIHISETLEQKPHFESSTVKTETISFGS
  VSPGGVKLEISTKEVPVVHTETKTITYESSQVDPGTDLEPGVLMSAQTITSETTSTTTTT
  HITKTVKGGISETRIEKRIVITGDADIDHDQALAQAIKEAKEQHPDMSVTKVVVHKETEI
  TPEDGED
• Function: Tumor suppressor that inhibits cell proliferation and promotes apoptosis. Modulates the activity of protein arginine N-methyltransferases, including PRMT3 and PRMT5.
• Tissue Specificity: Expressed at high levels in brain, with lower levels in kidney, intestine, and testis. Detected in lung.
• Reactome Pathway:
  Sensory processing of sound by inner hair cells of the cochlea (R-HSA-9662360)
  Sensory processing of sound by outer hair cells of the cochlea (R-HSA-9662361)
  Neurexins and neuroligins (R-HSA-6794361)

Molecular Interaction Atlas (MIA) of This DOT

37 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Adenocarcinoma	DIS3IHTY	Definitive	Posttranslational Modification	[1]
Ependymoma	DISUMRNZ	Definitive	Genetic Variation	[2]
Lung cancer	DISCM4YA	Definitive	Altered Expression	[3]
Lung carcinoma	DISTR26C	Definitive	Altered Expression	[3]
Meningioma	DISPT4TG	Definitive	Altered Expression	[3]
Neurofibromatosis type 2	DISI8ECS	Definitive	Biomarker	[4]
Squamous cell carcinoma	DISQVIFL	Definitive	Biomarker	[1]
Advanced cancer	DISAT1Z9	Strong	Biomarker	[5]
Brain neoplasm	DISY3EKS	Strong	Biomarker	[6]
Breast cancer	DIS7DPX1	Strong	Biomarker	[7]
Breast carcinoma	DIS2UE88	Strong	Biomarker	[7]
Cervical Intraepithelial neoplasia	DISXP757	Strong	Posttranslational Modification	[8]
Clear cell renal carcinoma	DISBXRFJ	Strong	Altered Expression	[9]
Cryptococcosis	DISDYDTK	Strong	Biomarker	[10]
Dysplasia of cervix	DISOAROS	Strong	Biomarker	[11]
Esophageal squamous cell carcinoma	DIS5N2GV	Strong	Biomarker	[12]
Lung neoplasm	DISVARNB	Strong	Posttranslational Modification	[13]
Metastatic malignant neoplasm	DIS86UK6	Strong	Biomarker	[14]
Neoplasm	DISZKGEW	Strong	Altered Expression	[5]
Oropharyngeal cancer	DISDAMTJ	Strong	Genetic Variation	[15]
Oropharyngeal carcinoma	DIS7K3AI	Strong	Genetic Variation	[15]
Prostate cancer	DISF190Y	Strong	Altered Expression	[16]
Prostate carcinoma	DISMJPLE	Strong	Altered Expression	[16]
Prostate neoplasm	DISHDKGQ	Strong	Biomarker	[17]
Schizophrenia	DISSRV2N	Strong	Altered Expression	[18]
Small-cell lung cancer	DISK3LZD	Strong	Altered Expression	[13]
T-cell lymphoma	DISSXRTQ	Strong	Posttranslational Modification	[19]
Carcinoma	DISH9F1N	moderate	Altered Expression	[14]
Hepatocellular carcinoma	DIS0J828	moderate	Altered Expression	[20]
Lung adenocarcinoma	DISD51WR	Disputed	Altered Expression	[21]
Breast neoplasm	DISNGJLM	Limited	Posttranslational Modification	[22]
Epithelial ovarian cancer	DIS56MH2	Limited	Biomarker	[23]
Gastric cancer	DISXGOUK	Limited	Altered Expression	[24]
Non-small-cell lung cancer	DIS5Y6R9	Limited	Biomarker	[12]
Ovarian cancer	DISZJHAP	Limited	Biomarker	[23]
Ovarian neoplasm	DISEAFTY	Limited	Biomarker	[23]
Stomach cancer	DISKIJSX	Limited	Altered Expression	[24]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Etoposide	DMNH3PG	Approved	Band 4.1-like protein 3 (EPB41L3) affects the response to substance of Etoposide.	[43]

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 Band 4.1-like protein 3 (EPB41L3).	[25]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene increases the methylation of Band 4.1-like protein 3 (EPB41L3).	[37]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Tretinoin	DM49DUI	Approved	Tretinoin increases the expression of Band 4.1-like protein 3 (EPB41L3).	[26]
Cisplatin	DMRHGI9	Approved	Cisplatin increases the expression of Band 4.1-like protein 3 (EPB41L3).	[27]
Estradiol	DMUNTE3	Approved	Estradiol increases the expression of Band 4.1-like protein 3 (EPB41L3).	[28]
Arsenic	DMTL2Y1	Approved	Arsenic affects the expression of Band 4.1-like protein 3 (EPB41L3).	[29]
Temozolomide	DMKECZD	Approved	Temozolomide increases the expression of Band 4.1-like protein 3 (EPB41L3).	[30]
Calcitriol	DM8ZVJ7	Approved	Calcitriol increases the expression of Band 4.1-like protein 3 (EPB41L3).	[31]
Testosterone	DM7HUNW	Approved	Testosterone increases the expression of Band 4.1-like protein 3 (EPB41L3).	[31]
Triclosan	DMZUR4N	Approved	Triclosan decreases the expression of Band 4.1-like protein 3 (EPB41L3).	[32]
Decitabine	DMQL8XJ	Approved	Decitabine affects the expression of Band 4.1-like protein 3 (EPB41L3).	[22]
Panobinostat	DM58WKG	Approved	Panobinostat increases the expression of Band 4.1-like protein 3 (EPB41L3).	[34]
Hydroquinone	DM6AVR4	Approved	Hydroquinone increases the expression of Band 4.1-like protein 3 (EPB41L3).	[35]
Mifepristone	DMGZQEF	Approved	Mifepristone increases the expression of Band 4.1-like protein 3 (EPB41L3).	[36]
SNDX-275	DMH7W9X	Phase 3	SNDX-275 increases the expression of Band 4.1-like protein 3 (EPB41L3).	[34]
Belinostat	DM6OC53	Phase 2	Belinostat increases the expression of Band 4.1-like protein 3 (EPB41L3).	[34]
(+)-JQ1	DM1CZSJ	Phase 1	(+)-JQ1 decreases the expression of Band 4.1-like protein 3 (EPB41L3).	[38]
PMID28460551-Compound-2	DM4DOUB	Patented	PMID28460551-Compound-2 decreases the expression of Band 4.1-like protein 3 (EPB41L3).	[39]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A increases the expression of Band 4.1-like protein 3 (EPB41L3).	[40]
Trichostatin A	DM9C8NX	Investigative	Trichostatin A increases the expression of Band 4.1-like protein 3 (EPB41L3).	[41]
Formaldehyde	DM7Q6M0	Investigative	Formaldehyde increases the expression of Band 4.1-like protein 3 (EPB41L3).	[42]

References

• [1] Differential role of gene hypermethylation in adenocarcinomas, squamous cell carcinomas and cervical intraepithelial lesions of the uterine cervix.Pathol Int. 2015 Sep;65(9):476-85. doi: 10.1111/pin.12332. Epub 2015 Jul 27.
• [2] Genetic differences on intracranial versus spinal cord ependymal tumors: a meta-analysis of genetic researches.Eur Spine J. 2016 Dec;25(12):3942-3951. doi: 10.1007/s00586-016-4745-4. Epub 2016 Sep 16.
• [3] Pivotal roles of protein 4.1B/DAL?, a FERMdomain containing protein, in tumor progression (Review).Int J Oncol. 2019 Nov;55(5):979-987. doi: 10.3892/ijo.2019.4877. Epub 2019 Sep 13.
• [4] Pathological classification and molecular genetics of meningiomas.J Neurooncol. 2010 Sep;99(3):379-91. doi: 10.1007/s11060-010-0342-2. Epub 2010 Sep 1.
• [5] miR-452 promotes the development of gastric cancer via targeting EPB41L3.Pathol Res Pract. 2020 Jan;216(1):152725. doi: 10.1016/j.prp.2019.152725. Epub 2019 Oct 31.
• [6] Loss of DAL-1, a protein 4.1-related tumor suppressor, is an important early event in the pathogenesis of meningiomas.Hum Mol Genet. 2000 Jun 12;9(10):1495-500. doi: 10.1093/hmg/9.10.1495.
• [7] CDK10 is not a target for aberrant DNA methylation in breast cancer.Anticancer Res. 2009 Oct;29(10):3939-44.
• [8] Associations of human gene EPB41L3 DNA methylation and cervical intraepithelial neoplasia in women living with HIV-1 in Africa.AIDS. 2018 Sep 24;32(15):2227-2236. doi: 10.1097/QAD.0000000000001932.
• [9] Aberrations of a cell adhesion molecule CADM4 in renal clear cell carcinoma.Int J Cancer. 2012 Mar 15;130(6):1329-37. doi: 10.1002/ijc.26160. Epub 2011 Jul 21.
• [10] Characterization of the complete uric acid degradation pathway in the fungal pathogen Cryptococcus neoformans.PLoS One. 2013 May 7;8(5):e64292. doi: 10.1371/journal.pone.0064292. Print 2013.
• [11] Discovery and validation of candidate host DNA methylation markers for detection of cervical precancer and cancer.Int J Cancer. 2017 Aug 15;141(4):701-710. doi: 10.1002/ijc.30781. Epub 2017 May 26.
• [12] EPB41L3 is a potential tumor suppressor gene and prognostic indicator in esophageal squamous cell carcinoma.Int J Oncol. 2018 May;52(5):1443-1454. doi: 10.3892/ijo.2018.4316. Epub 2018 Mar 14.
• [13] Expression and methylation pattern of TSLC1 cascade genes in lung carcinomas.Oncogene. 2006 Feb 9;25(6):959-68. doi: 10.1038/sj.onc.1209115.
• [14] DAL-1 attenuates epithelial-to mesenchymal transition in lung cancer.J Exp Clin Cancer Res. 2015 Jan 22;34(1):3. doi: 10.1186/s13046-014-0117-2.
• [15] Methylation of HPV 16 and EPB41L3 in oral gargles: Associations with oropharyngeal cancer detection and tumor characteristics.Int J Cancer. 2020 Feb 15;146(4):1018-1030. doi: 10.1002/ijc.32570. Epub 2019 Jul 26.
• [16] Factor interaction analysis for chromosome 8 and DNA methylation alterations highlights innate immune response suppression and cytoskeletal changes in prostate cancer.Mol Cancer. 2007 Feb 5;6:14. doi: 10.1186/1476-4598-6-14.
• [17] Potential role of EPB41L3 (protein 4.1B/Dal-1) as a target for treatment of advanced prostate cancer.Expert Opin Ther Targets. 2008 Jul;12(7):845-53. doi: 10.1517/14728222.12.7.845.
• [18] Prefrontal cortex shotgun proteome analysis reveals altered calcium homeostasis and immune system imbalance in schizophrenia.Eur Arch Psychiatry Clin Neurosci. 2009 Apr;259(3):151-63. doi: 10.1007/s00406-008-0847-2. Epub 2009 Jan 22.
• [19] Frequent concomitant epigenetic silencing of the stress-responsive tumor suppressor gene CADM1, and its interacting partner DAL-1 in nasal NK/T-cell lymphoma.Int J Cancer. 2009 Apr 1;124(7):1572-8. doi: 10.1002/ijc.24123.
• [20] LINC00052 upregulates EPB41L3 to inhibit migration and invasion of hepatocellular carcinoma by binding miR-452-5p.Oncotarget. 2017 Jun 29;8(38):63724-63737. doi: 10.18632/oncotarget.18892. eCollection 2017 Sep 8.
• [21] DAL-1 attenuates epithelial to mesenchymal transition and metastasis by suppressing HSPA5 expression in non-small cell lung cancer.Oncol Rep. 2017 Nov;38(5):3103-3113. doi: 10.3892/or.2017.6000. Epub 2017 Sep 26.
• [22] Downregulation of TSLC1 and DAL-1 expression occurs frequently in breast cancer. Breast Cancer Res Treat. 2007 Jul;103(3):283-91. doi: 10.1007/s10549-006-9377-7. Epub 2007 Jan 27.
• [23] Microcell-mediated chromosome transfer identifies EPB41L3 as a functional suppressor of epithelial ovarian cancers.Neoplasia. 2010 Jul;12(7):579-89. doi: 10.1593/neo.10340.
• [24] Decreased expression levels of DAL-1 and TOB1 are associated with clinicopathological features and poor prognosis in gastric cancer.Pathol Res Pract. 2019 Jun;215(6):152403. doi: 10.1016/j.prp.2019.03.031. Epub 2019 Apr 2.
• [25] 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.
• [26] 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.
• [27] 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.
• [28] 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.
• [29] Drinking-water arsenic exposure modulates gene expression in human lymphocytes from a U.S. population. Environ Health Perspect. 2008 Apr;116(4):524-31. doi: 10.1289/ehp.10861.
• [30] 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.
• [31] Effects of 1alpha,25 dihydroxyvitamin D3 and testosterone on miRNA and mRNA expression in LNCaP cells. Mol Cancer. 2011 May 18;10:58.
• [32] Transcriptome and DNA methylome dynamics during triclosan-induced cardiomyocyte differentiation toxicity. Stem Cells Int. 2018 Oct 29;2018:8608327.
• [33] Downregulation of TSLC1 and DAL-1 expression occurs frequently in breast cancer. Breast Cancer Res Treat. 2007 Jul;103(3):283-91. doi: 10.1007/s10549-006-9377-7. Epub 2007 Jan 27.
• [34] 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.
• [35] Keratinocyte-derived IL-36gama plays a role in hydroquinone-induced chemical leukoderma through inhibition of melanogenesis in human epidermal melanocytes. Arch Toxicol. 2019 Aug;93(8):2307-2320.
• [36] Mifepristone induced progesterone withdrawal reveals novel regulatory pathways in human endometrium. Mol Hum Reprod. 2007 Sep;13(9):641-54.
• [37] 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.
• [38] 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.
• [39] 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.
• [40] Low-dose Bisphenol A exposure alters the functionality and cellular environment in a human cardiomyocyte model. Environ Pollut. 2023 Oct 15;335:122359. doi: 10.1016/j.envpol.2023.122359. Epub 2023 Aug 9.
• [41] 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.
• [42] Cystathionine metabolic enzymes play a role in the inflammation resolution of human keratinocytes in response to sub-cytotoxic formaldehyde exposure. Toxicol Appl Pharmacol. 2016 Nov 1;310:185-194.
• [43] Gene expression profiling of 30 cancer cell lines predicts resistance towards 11 anticancer drugs at clinically achieved concentrations. Int J Cancer. 2006 Apr 1;118(7):1699-712. doi: 10.1002/ijc.21570.