Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OT37FKH0)

• DOT Name: Ubiquitin carboxyl-terminal hydrolase CYLD (CYLD)
• Synonyms: EC 3.4.19.12; Deubiquitinating enzyme CYLD; Ubiquitin thioesterase CYLD; Ubiquitin-specific-processing protease CYLD
• Gene Name: CYLD
• Related Disease:
  Brooke-Spiegler syndrome
  Familial cylindromatosis
  Melanoma
  Ovarian cancer
  Adenocarcinoma
  Alkaptonuria
  Alzheimer disease
  Amyloidosis
  Barrett esophagus
  Carcinoma of esophagus
  Clear cell renal carcinoma
  Crohn disease
  Dental caries
  Esophageal adenocarcinoma
  Frontotemporal dementia and/or amyotrophic lateral sclerosis 8
  Gastric adenocarcinoma
  Gastric cancer
  Hepatocellular carcinoma
  Lung adenocarcinoma
  Lung cancer
  Lung carcinoma
  Malignant thymoma
  Small lymphocytic lymphoma
  Squamous cell carcinoma
  Stomach cancer
  Trichoepithelioma, multiple familial, 1
  Urinary tract infection
  Asthma
  Carcinoma
  Glioblastoma multiforme
  Listeriosis
  Metastatic malignant neoplasm
  Skin cancer
  Familial multiple trichoepithelioma
  Amyotrophic lateral sclerosis
  B-cell neoplasm
  Breast cancer
  Breast carcinoma
  Cervical cancer
  Epithelial ovarian cancer
  Gastroesophageal reflux disease
  Glioma
  Neuroblastoma
  Non-small-cell lung cancer
  Rheumatoid arthritis
  Skin neoplasm
  T-cell leukaemia
  Uterine cervix neoplasm
• UniProt ID: CYLD_HUMAN
• PDB ID: 1IXD; 1WHL; 1WHM; 2VHF; 7OWC; 7OWD
• EC Number: 3.4.19.12
• Pfam ID: PF01302 ; PF16607 ; PF00443
• Sequence:
  MSSGLWSQEKVTSPYWEERIFYLLLQECSVTDKQTQKLLKVPKGSIGQYIQDRSVGHSRI
  PSAKGKKNQIGLKILEQPHAVLFVDEKDVVEINEKFTELLLAITNCEERFSLFKNRNRLS
  KGLQIDVGCPVKVQLRSGEEKFPGVVRFRGPLLAERTVSGIFFGVELLEEGRGQGFTDGV
  YQGKQLFQCDEDCGVFVALDKLELIEDDDTALESDYAGPGDTMQVELPPLEINSRVSLKV
  GETIESGTVIFCDVLPGKESLGYFVGVDMDNPIGNWDGRFDGVQLCSFACVESTILLHIN
  DIIPALSESVTQERRPPKLAFMSRGVGDKGSSSHNKPKATGSTSDPGNRNRSELFYTLNG
  SSVDSQPQSKSKNTWYIDEVAEDPAKSLTEISTDFDRSSPPLQPPPVNSLTTENRFHSLP
  FSLTKMPNTNGSIGHSPLSLSAQSVMEELNTAPVQESPPLAMPPGNSHGLEVGSLAEVKE
  NPPFYGVIRWIGQPPGLNEVLAGLELEDECAGCTDGTFRGTRYFTCALKKALFVKLKSCR
  PDSRFASLQPVSNQIERCNSLAFGGYLSEVVEENTPPKMEKEGLEIMIGKKKGIQGHYNS
  CYLDSTLFCLFAFSSVLDTVLLRPKEKNDVEYYSETQELLRTEIVNPLRIYGYVCATKIM
  KLRKILEKVEAASGFTSEEKDPEEFLNILFHHILRVEPLLKIRSAGQKVQDCYFYQIFME
  KNEKVGVPTIQQLLEWSFINSNLKFAEAPSCLIIQMPRFGKDFKLFKKIFPSLELNITDL
  LEDTPRQCRICGGLAMYECRECYDDPDISAGKIKQFCKTCNTQVHLHPKRLNHKYNPVSL
  PKDLPDWDWRHGCIPCQNMELFAVLCIETSHYVAFVKYGKDDSAWLFFDSMADRDGGQNG
  FNIPQVTPCPEVGEYLKMSLEDLHSLDSRRIQGCARRLLCDAYMCMYQSPTMSLYK
• Function: Deubiquitinase that specifically cleaves 'Lys-63'- and linear 'Met-1'-linked polyubiquitin chains and is involved in NF-kappa-B activation and TNF-alpha-induced necroptosis. Negatively regulates NF-kappa-B activation by deubiquitinating upstream signaling factors. Contributes to the regulation of cell survival, proliferation and differentiation via its effects on NF-kappa-B activation. Negative regulator of Wnt signaling. Inhibits HDAC6 and thereby promotes acetylation of alpha-tubulin and stabilization of microtubules. Plays a role in the regulation of microtubule dynamics, and thereby contributes to the regulation of cell proliferation, cell polarization, cell migration, and angiogenesis. Required for normal cell cycle progress and normal cytokinesis. Inhibits nuclear translocation of NF-kappa-B. Plays a role in the regulation of inflammation and the innate immune response, via its effects on NF-kappa-B activation. Dispensable for the maturation of intrathymic natural killer cells, but required for the continued survival of immature natural killer cells. Negatively regulates TNFRSF11A signaling and osteoclastogenesis. Involved in the regulation of ciliogenesis, allowing ciliary basal bodies to migrate and dock to the plasma membrane; this process does not depend on NF-kappa-B activation. Ability to remove linear ('Met-1'-linked) polyubiquitin chains regulates innate immunity and TNF-alpha-induced necroptosis: recruited to the LUBAC complex via interaction with SPATA2 and restricts linear polyubiquitin formation on target proteins. Regulates innate immunity by restricting linear polyubiquitin formation on RIPK2 in response to NOD2 stimulation. Involved in TNF-alpha-induced necroptosis by removing linear ('Met-1'-linked) polyubiquitin chains from RIPK1, thereby regulating the kinase activity of RIPK1. Negatively regulates intestinal inflammation by removing 'Lys-63' linked polyubiquitin chain of NLRP6, thereby reducing the interaction between NLRP6 and PYCARD/ASC and formation of the NLRP6 inflammasome. Removes 'Lys-63' linked polyubiquitin chain of MAP3K7, which inhibits phosphorylation and blocks downstream activation of the JNK-p38 kinase cascades. Removes also 'Lys-63'-linked polyubiquitin chains of MAP3K1 and MA3P3K3, which inhibit their interaction with MAP2K1 and MAP2K2.
• Tissue Specificity: Detected in fetal brain, testis, and skeletal muscle, and at a lower level in adult brain, leukocytes, liver, heart, kidney, spleen, ovary and lung. Isoform 2 is found in all tissues except kidney.
• KEGG Pathway:
  NF-kappa B sig.ling pathway (hsa04064)
  Necroptosis (hsa04217)
  Osteoclast differentiation (hsa04380)
  RIG-I-like receptor sig.ling pathway (hsa04622)
  C-type lectin receptor sig.ling pathway (hsa04625)
  TNF sig.ling pathway (hsa04668)
• Reactome Pathway:
  TNFR1-induced proapoptotic signaling (R-HSA-5357786)
  Regulation of TNFR1 signaling (R-HSA-5357905)
  TNFR1-induced NF-kappa-B signaling pathway (R-HSA-5357956)
  Ub-specific processing proteases (R-HSA-5689880)
  Negative regulators of DDX58/IFIH1 signaling (R-HSA-936440)
  NOD1/2 Signaling Pathway (R-HSA-168638)

Molecular Interaction Atlas (MIA) of This DOT

48 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Brooke-Spiegler syndrome	DIS36OT6	Definitive	Autosomal dominant	[1]
Familial cylindromatosis	DIS2W9ZC	Definitive	Autosomal dominant	[2]
Melanoma	DIS1RRCY	Definitive	Biomarker	[3]
Ovarian cancer	DISZJHAP	Definitive	Biomarker	[3]
Adenocarcinoma	DIS3IHTY	Strong	Altered Expression	[4]
Alkaptonuria	DISXDZWS	Strong	Biomarker	[5]
Alzheimer disease	DISF8S70	Strong	Biomarker	[6]
Amyloidosis	DISHTAI2	Strong	Biomarker	[7]
Barrett esophagus	DIS416Y7	Strong	Biomarker	[8]
Carcinoma of esophagus	DISS6G4D	Strong	Biomarker	[9]
Clear cell renal carcinoma	DISBXRFJ	Strong	Altered Expression	[10]
Crohn disease	DIS2C5Q8	Strong	Altered Expression	[11]
Dental caries	DISRBCMD	Strong	Biomarker	[12]
Esophageal adenocarcinoma	DISODWFP	Strong	Genetic Variation	[13]
Frontotemporal dementia and/or amyotrophic lateral sclerosis 8	DISQKJPH	Strong	Autosomal dominant	[14]
Gastric adenocarcinoma	DISWWLTC	Strong	Posttranslational Modification	[15]
Gastric cancer	DISXGOUK	Strong	Altered Expression	[15]
Hepatocellular carcinoma	DIS0J828	Strong	Altered Expression	[16]
Lung adenocarcinoma	DISD51WR	Strong	Biomarker	[17]
Lung cancer	DISCM4YA	Strong	Altered Expression	[18]
Lung carcinoma	DISTR26C	Strong	Altered Expression	[18]
Malignant thymoma	DIS59MOU	Strong	Biomarker	[19]
Small lymphocytic lymphoma	DIS30POX	Strong	Biomarker	[20]
Squamous cell carcinoma	DISQVIFL	Strong	Altered Expression	[21]
Stomach cancer	DISKIJSX	Strong	Altered Expression	[15]
Trichoepithelioma, multiple familial, 1	DIS2BOFP	Strong	Autosomal dominant	[22]
Urinary tract infection	DISMT6UV	Strong	Biomarker	[23]
Asthma	DISW9QNS	moderate	Genetic Variation	[24]
Carcinoma	DISH9F1N	moderate	Genetic Variation	[25]
Glioblastoma multiforme	DISK8246	moderate	Biomarker	[26]
Listeriosis	DISKMQBM	moderate	Biomarker	[27]
Metastatic malignant neoplasm	DIS86UK6	moderate	Genetic Variation	[28]
Skin cancer	DISTM18U	moderate	Biomarker	[29]
Familial multiple trichoepithelioma	DISKZAUY	Supportive	Autosomal dominant	[30]
Amyotrophic lateral sclerosis	DISF7HVM	Limited	Autosomal dominant	[31]
B-cell neoplasm	DISVY326	Limited	Altered Expression	[32]
Breast cancer	DIS7DPX1	Limited	Biomarker	[33]
Breast carcinoma	DIS2UE88	Limited	Biomarker	[33]
Cervical cancer	DISFSHPF	Limited	Biomarker	[34]
Epithelial ovarian cancer	DIS56MH2	Limited	Biomarker	[3]
Gastroesophageal reflux disease	DISQ8G5S	Limited	Genetic Variation	[35]
Glioma	DIS5RPEH	Limited	Biomarker	[36]
Neuroblastoma	DISVZBI4	Limited	Altered Expression	[37]
Non-small-cell lung cancer	DIS5Y6R9	Limited	Biomarker	[38]
Rheumatoid arthritis	DISTSB4J	Limited	Biomarker	[39]
Skin neoplasm	DIS16DDV	Limited	Genetic Variation	[40]
T-cell leukaemia	DISJ6YIF	Limited	Altered Expression	[41]
Uterine cervix neoplasm	DIS0BYVV	Limited	Biomarker	[34]

This DOT Affected the Drug Response of 2 Drug(s)

Drug Name	Drug ID	Highest Status	Interaction	REF
Doxorubicin	DMVP5YE	Approved	Ubiquitin carboxyl-terminal hydrolase CYLD (CYLD) increases the response to substance of Doxorubicin.	[51]
Fluorouracil	DMUM7HZ	Approved	Ubiquitin carboxyl-terminal hydrolase CYLD (CYLD) increases the response to substance of Fluorouracil.	[51]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Valproate	DMCFE9I	Approved	Valproate increases the expression of Ubiquitin carboxyl-terminal hydrolase CYLD (CYLD).	[42]
Ciclosporin	DMAZJFX	Approved	Ciclosporin decreases the expression of Ubiquitin carboxyl-terminal hydrolase CYLD (CYLD).	[43]
Tretinoin	DM49DUI	Approved	Tretinoin increases the expression of Ubiquitin carboxyl-terminal hydrolase CYLD (CYLD).	[44]
Acetaminophen	DMUIE76	Approved	Acetaminophen increases the expression of Ubiquitin carboxyl-terminal hydrolase CYLD (CYLD).	[45]
Cisplatin	DMRHGI9	Approved	Cisplatin increases the expression of Ubiquitin carboxyl-terminal hydrolase CYLD (CYLD).	[46]
Arsenic trioxide	DM61TA4	Approved	Arsenic trioxide decreases the expression of Ubiquitin carboxyl-terminal hydrolase CYLD (CYLD).	[47]
Vorinostat	DMWMPD4	Approved	Vorinostat increases the expression of Ubiquitin carboxyl-terminal hydrolase CYLD (CYLD).	[48]
Triclosan	DMZUR4N	Approved	Triclosan decreases the expression of Ubiquitin carboxyl-terminal hydrolase CYLD (CYLD).	[49]
Cannabidiol	DM0659E	Approved	Cannabidiol increases the expression of Ubiquitin carboxyl-terminal hydrolase CYLD (CYLD).	[50]
Sorafenib	DMS8IFC	Approved	Sorafenib increases the expression of Ubiquitin carboxyl-terminal hydrolase CYLD (CYLD).	[51]
Nefazodone	DM4ZS8M	Approved	Nefazodone increases the expression of Ubiquitin carboxyl-terminal hydrolase CYLD (CYLD).	[52]
Atazanavir	DMSYRBX	Approved	Atazanavir increases the expression of Ubiquitin carboxyl-terminal hydrolase CYLD (CYLD).	[52]
Urethane	DM7NSI0	Phase 4	Urethane increases the expression of Ubiquitin carboxyl-terminal hydrolase CYLD (CYLD).	[53]
Leflunomide	DMR8ONJ	Phase 1 Trial	Leflunomide decreases the expression of Ubiquitin carboxyl-terminal hydrolase CYLD (CYLD).	[54]
Formaldehyde	DM7Q6M0	Investigative	Formaldehyde increases the expression of Ubiquitin carboxyl-terminal hydrolase CYLD (CYLD).	[56]
Glyphosate	DM0AFY7	Investigative	Glyphosate increases the expression of Ubiquitin carboxyl-terminal hydrolase CYLD (CYLD).	[57]
GALLICACID	DM6Y3A0	Investigative	GALLICACID decreases the expression of Ubiquitin carboxyl-terminal hydrolase CYLD (CYLD).	[58]
U0126	DM31OGF	Investigative	U0126 increases the expression of Ubiquitin carboxyl-terminal hydrolase CYLD (CYLD).	[51]
Tyrphostin Ag-1478	DM87ZIH	Investigative	Tyrphostin Ag-1478 increases the expression of Ubiquitin carboxyl-terminal hydrolase CYLD (CYLD).	[51]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A decreases the methylation of Ubiquitin carboxyl-terminal hydrolase CYLD (CYLD).	[55]

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] Two novel CYLD gene mutations in Chinese families with trichoepithelioma and a literature review of 16 families with trichoepithelioma reported in China. Br J Dermatol. 2005 Dec;153(6):1213-5. doi: 10.1111/j.1365-2133.2005.06960.x.
• [3] Cytotoxicity of Nubein6.8 peptide isolated from the snake venom of Naja nubiae on melanoma and ovarian carcinoma cell lines.Toxicon. 2019 Oct;168:22-31. doi: 10.1016/j.toxicon.2019.06.220. Epub 2019 Jun 21.
• [4] IL-33 drives the antitumour effects of dendritic cells via upregulating CYLD expression in pulmonary adenocarcinoma.Artif Cells Nanomed Biotechnol. 2019 Dec;47(1):1335-1341. doi: 10.1080/21691401.2019.1596926.
• [5] Cytoskeleton Aberrations in Alkaptonuric Chondrocytes.J Cell Physiol. 2017 Jul;232(7):1728-1738. doi: 10.1002/jcp.25500. Epub 2017 Jan 31.
• [6] Reducing INS-IGF1 signaling protects against non-cell autonomous vesicle rupture caused by SNCA spreading.Autophagy. 2020 May;16(5):878-899. doi: 10.1080/15548627.2019.1643657. Epub 2019 Jul 29.
• [7] Destabilization of -amyloid aggregates by thrombin derived peptide: plausible role of thrombin in neuroprotection.FEBS J. 2020 Jun;287(11):2386-2413. doi: 10.1111/febs.15149. Epub 2020 Jan 3.
• [8] Genome-wide tracts of homozygosity and exome analyses reveal repetitive elements with Barrets esophagus/esophageal adenocarcinoma risk.BMC Bioinformatics. 2019 Mar 14;20(Suppl 2):98. doi: 10.1186/s12859-019-2622-y.
• [9] Comparison of Inflammation-Based Prognostic Scores in a Cohort of Patients with Resectable Esophageal Cancer.Gastroenterol Res Pract. 2017;2017:1678584. doi: 10.1155/2017/1678584. Epub 2017 Jun 27.
• [10] Action of YM155 on clear cell renal cell carcinoma does not depend on survivin expression levels.PLoS One. 2017 Jun 5;12(6):e0178168. doi: 10.1371/journal.pone.0178168. eCollection 2017.
• [11] Alternative Splice Forms of CYLD Mediate Ubiquitination of SMAD7 to Prevent TGFB Signaling and Promote Colitis.Gastroenterology. 2019 Feb;156(3):692-707.e7. doi: 10.1053/j.gastro.2018.10.023. Epub 2018 Oct 10.
• [12] General and erosive tooth wear of 16-year-old adolescents in Kuantan, Malaysia: prevalence and association with dental caries.BMC Oral Health. 2018 Jan 12;18(1):11. doi: 10.1186/s12903-017-0451-9.
• [13] Expression, regulation and targeting of receptor tyrosine kinases in esophageal squamous cell carcinoma.Mol Cancer. 2018 Feb 19;17(1):54. doi: 10.1186/s12943-018-0790-4.
• [14] Frontotemporal dementia-amyotrophic lateral sclerosis syndrome locus on chromosome 16p12.1-q12.2: genetic, clinical and neuropathological analysis. Acta Neuropathol. 2013 Apr;125(4):523-33. doi: 10.1007/s00401-013-1078-9. Epub 2013 Jan 22.
• [15] Epigenetic alterations of CYLD promoter modulate its expression in gastric adenocarcinoma: A footprint of infections.J Cell Physiol. 2019 Apr;234(4):4115-4124. doi: 10.1002/jcp.27220. Epub 2018 Aug 21.
• [16] The expression of tumor suppressor gene Cyld is upregulated by histone deacetylace inhibitors in human hepatocellular carcinoma cell lines.Cell Biochem Funct. 2016 Oct;34(7):465-468. doi: 10.1002/cbf.3212. Epub 2016 Aug 29.
• [17] Design of Block Copolymer Micellar Aggregates for Co-Delivery of Enzyme and Anticancer Prodrug.Chem Asian J. 2017 Jan 17;12(2):176-180. doi: 10.1002/asia.201601198. Epub 2016 Dec 14.
• [18] Rig-G is a growth inhibitory factor of lung cancer cells that suppresses STAT3 and NF-B.Oncotarget. 2016 Oct 4;7(40):66032-66050. doi: 10.18632/oncotarget.11797.
• [19] A specific missense mutation in GTF2I occurs at high frequency in thymic epithelial tumors.Nat Genet. 2014 Aug;46(8):844-9. doi: 10.1038/ng.3016. Epub 2014 Jun 29.
• [20] Aberrant splicing of the tumor suppressor CYLD promotes the development of chronic lymphocytic leukemia via sustained NF-B signaling.Leukemia. 2018 Jan;32(1):72-82. doi: 10.1038/leu.2017.168. Epub 2017 Jun 1.
• [21] Phospho-Np63-responsive microRNAs contribute to the regulation of necroptosis in squamous cell carcinoma upon cisplatin exposure.FEBS Lett. 2015 May 22;589(12):1352-8. doi: 10.1016/j.febslet.2015.04.020. Epub 2015 Apr 21.
• [22] The Gene Curation Coalition: A global effort to harmonize gene-disease evidence resources. Genet Med. 2022 Aug;24(8):1732-1742. doi: 10.1016/j.gim.2022.04.017. Epub 2022 May 4.
• [23] Carbapenem-Resistant KPC- and TEM-Producing Escherichia coli ST131 Isolated from a Hospitalized Patient with Urinary Tract Infection: First Isolation in Molise Region, Central Italy, July 2018.Microb Drug Resist. 2020 Jan;26(1):38-45. doi: 10.1089/mdr.2019.0085. Epub 2019 Aug 6.
• [24] Identification of a new locus at 16q12 associated with time to asthma onset.J Allergy Clin Immunol. 2016 Oct;138(4):1071-1080. doi: 10.1016/j.jaci.2016.03.018. Epub 2016 Apr 6.
• [25] An inactivating CYLD mutation promotes skin tumor progression by conferring enhanced proliferative, survival and angiogenic properties to epidermal cancer cells.Oncogene. 2010 Dec 16;29(50):6522-32. doi: 10.1038/onc.2010.378. Epub 2010 Sep 13.
• [26] Molecularly Targeted Drugs Plus Radiotherapy and Temozolomide Treatment for Newly Diagnosed Glioblastoma: A Meta-Analysis and Systematic Review.Oncol Res. 2016;24(2):117-28. doi: 10.3727/096504016X14612603423511.
• [27] CYLD enhances severe listeriosis by impairing IL-6/STAT3-dependent fibrin production.PLoS Pathog. 2013;9(6):e1003455. doi: 10.1371/journal.ppat.1003455. Epub 2013 Jun 27.
• [28] Targeted genomic sequencing of follicular dendritic cell sarcoma reveals recurrent alterations in NF-B regulatory genes.Mod Pathol. 2016 Jan;29(1):67-74. doi: 10.1038/modpathol.2015.130. Epub 2015 Nov 13.
• [29] CYLD inhibits tumorigenesis and metastasis by blocking JNK/AP1 signaling at multiple levels.Cancer Prev Res (Phila). 2011 Jun;4(6):851-9. doi: 10.1158/1940-6207.CAPR-10-0360. Epub 2011 Apr 8.
• [30] Update of cylindromatosis gene (CYLD) mutations in Brooke-Spiegler syndrome: novel insights into the role of deubiquitination in cell signaling. Hum Mutat. 2009 Jul;30(7):1025-36. doi: 10.1002/humu.21024.
• [31] Classification of Genes: Standardized Clinical Validity Assessment of Gene-Disease Associations Aids Diagnostic Exome Analysis and Reclassifications. Hum Mutat. 2017 May;38(5):600-608. doi: 10.1002/humu.23183. Epub 2017 Feb 13.
• [32] UVB radiation represses CYLD expression in melanocytes.Oncol Lett. 2017 Dec;14(6):7262-7268. doi: 10.3892/ol.2017.7120. Epub 2017 Oct 3.
• [33] Rutin and orlistat produce antitumor effects via antioxidant and apoptotic actions.Naunyn Schmiedebergs Arch Pharmacol. 2019 Feb;392(2):165-175. doi: 10.1007/s00210-018-1579-0. Epub 2018 Nov 21.
• [34] miR-501 is upregulated in cervical cancer and promotes cell proliferation, migration and invasion by targeting CYLD.Chem Biol Interact. 2018 Apr 1;285:85-95. doi: 10.1016/j.cbi.2018.02.024. Epub 2018 Feb 23.
• [35] Esophageal Adenocarcinoma After Antireflux Surgery in a Cohort Study From the 5 Nordic Countries.Ann Surg. 2021 Dec 1;274(6):e535-e540. doi: 10.1097/SLA.0000000000003709.
• [36] Tie2 identifies a hematopoietic lineage of proangiogenic monocytes required for tumor vessel formation and a mesenchymal population of pericyte progenitors.Cancer Cell. 2005 Sep;8(3):211-26. doi: 10.1016/j.ccr.2005.08.002.
• [37] Deubiquitinating activity of CYLD is impaired by SUMOylation in neuroblastoma cells.Oncogene. 2015 Apr 23;34(17):2251-60. doi: 10.1038/onc.2014.159. Epub 2014 Jun 9.
• [38] Pharmacologic inhibition of epigenetic modifications, coupled with gene expression profiling, reveals novel targets of aberrant DNA methylation and histone deacetylation in lung cancer.Oncogene. 2007 Apr 19;26(18):2621-34. doi: 10.1038/sj.onc.1210041. Epub 2006 Oct 9.
• [39] Refining the complex rheumatoid arthritis phenotype based on specificity of the HLA-DRB1 shared epitope for antibodies to citrullinated proteins.Arthritis Rheum. 2005 Nov;52(11):3433-8. doi: 10.1002/art.21385.
• [40] Epigenetic modifiers DNMT3A and BCOR are recurrently mutated in CYLD cutaneous syndrome.Nat Commun. 2019 Oct 17;10(1):4717. doi: 10.1038/s41467-019-12746-w.
• [41] Hes1 expression and CYLD repression are essential events downstream of Notch1 in T-cell leukemia.Cell Cycle. 2011 Apr 1;10(7):1031-6. doi: 10.4161/cc.10.7.15067. Epub 2011 Apr 1.
• [42] The neuroprotective action of the mood stabilizing drugs lithium chloride and sodium valproate is mediated through the up-regulation of the homeodomain protein Six1. Toxicol Appl Pharmacol. 2009 Feb 15;235(1):124-34.
• [43] Integrating multiple omics to unravel mechanisms of Cyclosporin A induced hepatotoxicity in vitro. Toxicol In Vitro. 2015 Apr;29(3):489-501.
• [44] 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.
• [45] Multiple microRNAs function as self-protective modules in acetaminophen-induced hepatotoxicity in humans. Arch Toxicol. 2018 Feb;92(2):845-858.
• [46] 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.
• [47] Arsenic suppresses gene expression in promyelocytic leukemia cells partly through Sp1 oxidation. Blood. 2005 Jul 1;106(1):304-10.
• [48] A genomic approach to predict synergistic combinations for breast cancer treatment. Pharmacogenomics J. 2013 Feb;13(1):94-104. doi: 10.1038/tpj.2011.48. Epub 2011 Nov 15.
• [49] Primary Human Hepatocyte Spheroids as Tools to Study the Hepatotoxic Potential of Non-Pharmaceutical Chemicals. Int J Mol Sci. 2021 Oct 12;22(20):11005. doi: 10.3390/ijms222011005.
• [50] Transcriptomic Analysis of Stem Cells Treated with Moringin or Cannabidiol: Analogies and Differences in Inflammation Pathways. Int J Mol Sci. 2019 Nov 30;20(23):6039. doi: 10.3390/ijms20236039.
• [51] Down-regulation of CYLD as a trigger for NF-B activation and a mechanism of apoptotic resistance in hepatocellular carcinoma cells. Int J Oncol. 2011 Jan;38(1):121-31.
• [52] Robustness testing and optimization of an adverse outcome pathway on cholestatic liver injury. Arch Toxicol. 2020 Apr;94(4):1151-1172. doi: 10.1007/s00204-020-02691-9. Epub 2020 Mar 10.
• [53] Ethyl carbamate induces cell death through its effects on multiple metabolic pathways. Chem Biol Interact. 2017 Nov 1;277:21-32.
• [54] Endoplasmic reticulum stress and MAPK signaling pathway activation underlie leflunomide-induced toxicity in HepG2 Cells. Toxicology. 2017 Dec 1;392:11-21.
• [55] 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.
• [56] Characterization of formaldehyde's genotoxic mode of action by gene expression analysis in TK6 cells. Arch Toxicol. 2013 Nov;87(11):1999-2012.
• [57] Use of human neuroblastoma SH-SY5Y cells to evaluate glyphosate-induced effects on oxidative stress, neuronal development and cell death signaling pathways. Environ Int. 2020 Feb;135:105414. doi: 10.1016/j.envint.2019.105414. Epub 2019 Dec 23.
• [58] Gene expression profile analysis of gallic acid-induced cell death process. Sci Rep. 2021 Aug 18;11(1):16743. doi: 10.1038/s41598-021-96174-1.
• [59] Down-regulation of CYLD as a trigger for NF-B activation and a mechanism of apoptotic resistance in hepatocellular carcinoma cells. Int J Oncol. 2011 Jan;38(1):121-31.