Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTBR6U9G)

• DOT Name: Protein FAM3C (FAM3C)
• Synonyms: Interleukin-like EMT inducer
• Gene Name: FAM3C
• Related Disease:
  Advanced cancer
  Alzheimer disease
  Anal intraepithelial neoplasia
  Breast cancer
  Breast carcinoma
  Coffin-Siris syndrome
  Esophageal squamous cell carcinoma
  Hepatocellular carcinoma
  Prostate cancer
  Prostate carcinoma
  Squamous cell carcinoma
  Lung cancer
  Lung carcinoma
  Metastatic malignant neoplasm
  Fatty liver disease
  Non-insulin dependent diabetes
  Gastric cancer
  Hyperglycemia
  Melanoma
  Neoplasm
  Stomach cancer
  Temporal lobe epilepsy
• UniProt ID: FAM3C_HUMAN
• PDB ID: 5LC2
• Pfam ID: PF15711
• Sequence:
  MRVAGAAKLVVAVAVFLLTFYVISQVFEIKMDASLGNLFARSALDTAARSTKPPRYKCGI
  SKACPEKHFAFKMASGAANVVGPKICLEDNVLMSGVKNNVGRGINVALANGKTGEVLDTK
  YFDMWGGDVAPFIEFLKAIQDGTIVLMGTYDDGATKLNDEARRLIADLGSTSITNLGFRD
  NWVFCGGKGIKTKSPFEQHIKNNKDTNKYEGWPEVVEMEGCIPQKQD
• Function: May be involved in retinal laminar formation. Promotes epithelial to mesenchymal transition.
• Tissue Specificity: Present in most secretory epithelia (at protein level).
• Reactome Pathway: Platelet degranulation (R-HSA-114608)

Molecular Interaction Atlas (MIA) of This DOT

22 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Advanced cancer	DISAT1Z9	Strong	Biomarker	[1]
Alzheimer disease	DISF8S70	Strong	Biomarker	[2]
Anal intraepithelial neoplasia	DISJ0JW3	Strong	Altered Expression	[1]
Breast cancer	DIS7DPX1	Strong	Biomarker	[3]
Breast carcinoma	DIS2UE88	Strong	Biomarker	[3]
Coffin-Siris syndrome	DIS8L03H	Strong	Genetic Variation	[4]
Esophageal squamous cell carcinoma	DIS5N2GV	Strong	Altered Expression	[5]
Hepatocellular carcinoma	DIS0J828	Strong	Biomarker	[6]
Prostate cancer	DISF190Y	Strong	Biomarker	[7]
Prostate carcinoma	DISMJPLE	Strong	Biomarker	[7]
Squamous cell carcinoma	DISQVIFL	Strong	Altered Expression	[1]
Lung cancer	DISCM4YA	moderate	Biomarker	[8]
Lung carcinoma	DISTR26C	moderate	Biomarker	[8]
Metastatic malignant neoplasm	DIS86UK6	moderate	Altered Expression	[9]
Fatty liver disease	DIS485QZ	Disputed	Altered Expression	[10]
Non-insulin dependent diabetes	DISK1O5Z	Disputed	Altered Expression	[10]
Gastric cancer	DISXGOUK	Limited	Biomarker	[11]
Hyperglycemia	DIS0BZB5	Limited	Altered Expression	[12]
Melanoma	DIS1RRCY	Limited	Biomarker	[13]
Neoplasm	DISZKGEW	Limited	Biomarker	[13]
Stomach cancer	DISKIJSX	Limited	Biomarker	[11]
Temporal lobe epilepsy	DISNOPXX	Limited	Biomarker	[14]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Paclitaxel	DMLB81S	Approved	Protein FAM3C (FAM3C) affects the response to substance of Paclitaxel.	[30]
Vinblastine	DM5TVS3	Approved	Protein FAM3C (FAM3C) affects the response to substance of Vinblastine.	[30]

2 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 Protein FAM3C (FAM3C).	[15]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A decreases the methylation of Protein FAM3C (FAM3C).	[26]

14 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 Protein FAM3C (FAM3C).	[16]
Acetaminophen	DMUIE76	Approved	Acetaminophen increases the expression of Protein FAM3C (FAM3C).	[17]
Cisplatin	DMRHGI9	Approved	Cisplatin decreases the expression of Protein FAM3C (FAM3C).	[18]
Ivermectin	DMDBX5F	Approved	Ivermectin decreases the expression of Protein FAM3C (FAM3C).	[19]
Vorinostat	DMWMPD4	Approved	Vorinostat decreases the expression of Protein FAM3C (FAM3C).	[20]
Isotretinoin	DM4QTBN	Approved	Isotretinoin decreases the expression of Protein FAM3C (FAM3C).	[21]
Irinotecan	DMP6SC2	Approved	Irinotecan decreases the expression of Protein FAM3C (FAM3C).	[22]
Alitretinoin	DMME8LH	Approved	Alitretinoin increases the expression of Protein FAM3C (FAM3C).	[16]
Urethane	DM7NSI0	Phase 4	Urethane increases the expression of Protein FAM3C (FAM3C).	[23]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene increases the expression of Protein FAM3C (FAM3C).	[25]
Trichostatin A	DM9C8NX	Investigative	Trichostatin A increases the expression of Protein FAM3C (FAM3C).	[27]
methyl p-hydroxybenzoate	DMO58UW	Investigative	methyl p-hydroxybenzoate decreases the expression of Protein FAM3C (FAM3C).	[28]
QUERCITRIN	DM1DH96	Investigative	QUERCITRIN increases the expression of Protein FAM3C (FAM3C).	[29]
all-trans-4-oxo-retinoic acid	DMM2R1N	Investigative	all-trans-4-oxo-retinoic acid increases the expression of Protein FAM3C (FAM3C).	[16]

1 Drug(s) Affected the Protein Interaction/Cellular Processes of This DOT

Drug Name	Drug ID	Highest Status	Interaction	REF
DNCB	DMDTVYC	Phase 2	DNCB affects the binding of Protein FAM3C (FAM3C).	[24]

References

• [1] Overexpression of FAM3C is associated with poor prognosis in oral squamous cell carcinoma.Pathol Res Pract. 2019 Apr;215(4):772-778. doi: 10.1016/j.prp.2019.01.019. Epub 2019 Jan 14.
• [2] Neuronal expression of ILEI/FAM3C and its reduction in Alzheimer's disease.Neuroscience. 2016 Aug 25;330:236-46. doi: 10.1016/j.neuroscience.2016.05.050. Epub 2016 May 30.
• [3] TGF promotes breast cancer stem cell self-renewal through an ILEI/LIFR signaling axis.Oncogene. 2019 May;38(20):3794-3811. doi: 10.1038/s41388-019-0703-z. Epub 2019 Jan 28.
• [4] Duplication of C7orf58, WNT16 and FAM3C in an obese female with a t(7;22)(q32.1;q11.2) chromosomal translocation and clinical features resembling Coffin-Siris Syndrome.PLoS One. 2012;7(12):e52353. doi: 10.1371/journal.pone.0052353. Epub 2012 Dec 27.
• [5] Prognostic significance of FAM3C in esophageal squamous cell carcinoma.Diagn Pathol. 2015 Oct 24;10:192. doi: 10.1186/s13000-015-0424-8.
• [6] ILEI requires oncogenic Ras for the epithelial to mesenchymal transition of hepatocytes and liver carcinoma progression.Oncogene. 2009 Feb 5;28(5):638-50. doi: 10.1038/onc.2008.418. Epub 2008 Nov 17.
• [7] The ubiquitin ligase UBE4A inhibits prostate cancer progression by targeting interleukin-like EMT inducer (ILEI).IUBMB Life. 2017 Jan;69(1):16-21. doi: 10.1002/iub.1585. Epub 2016 Nov 10.
• [8] ILEI drives epithelial to mesenchymal transition and metastatic progression in the lung cancer cell line A549.Tumour Biol. 2014 Feb;35(2):1377-82. doi: 10.1007/s13277-013-1188-y. Epub 2013 Sep 27.
• [9] Interleukin-like EMT inducer regulates partial phenotype switching in MITF-low melanoma cell lines.PLoS One. 2017 May 17;12(5):e0177830. doi: 10.1371/journal.pone.0177830. eCollection 2017.
• [10] Hepatic Activation of the FAM3C-HSF1-CaM Pathway Attenuates Hyperglycemia of Obese Diabetic Mice.Diabetes. 2017 May;66(5):1185-1197. doi: 10.2337/db16-0993. Epub 2017 Feb 28.
• [11] Elevated FAM3C promotes cell epithelial- mesenchymal transition and cell migration in gastric cancer.Onco Targets Ther. 2018 Dec 5;11:8491-8505. doi: 10.2147/OTT.S178455. eCollection 2018.
• [12] FAM3C activates HSF1 to suppress hepatic gluconeogenesis and attenuate hyperglycemia of type 1 diabetic mice.Oncotarget. 2017 Nov 20;8(62):106038-106049. doi: 10.18632/oncotarget.22524. eCollection 2017 Dec 1.
• [13] Interleukin-like EMT inducer (ILEI) promotes melanoma invasiveness and is transcriptionally up-regulated by upstream stimulatory factor-1 (USF-1).J Biol Chem. 2018 Jul 20;293(29):11401-11414. doi: 10.1074/jbc.RA118.003616. Epub 2018 Jun 5.
• [14] Proteomic analysis of cerebrospinal fluid from patients with idiopathic temporal lobe epilepsy.Brain Res. 2009 Feb 19;1255:180-9. doi: 10.1016/j.brainres.2008.12.008. Epub 2008 Dec 11.
• [15] 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.
• [16] Retinoic acid and its 4-oxo metabolites are functionally active in human skin cells in vitro. J Invest Dermatol. 2005 Jul;125(1):143-53.
• [17] Multiple microRNAs function as self-protective modules in acetaminophen-induced hepatotoxicity in humans. Arch Toxicol. 2018 Feb;92(2):845-858.
• [18] 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.
• [19] 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.
• [20] 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.
• [21] Temporal changes in gene expression in the skin of patients treated with isotretinoin provide insight into its mechanism of action. Dermatoendocrinol. 2009 May;1(3):177-87.
• [22] Clinical determinants of response to irinotecan-based therapy derived from cell line models. Clin Cancer Res. 2008 Oct 15;14(20):6647-55.
• [23] Ethyl carbamate induces cell death through its effects on multiple metabolic pathways. Chem Biol Interact. 2017 Nov 1;277:21-32.
• [24] Proteomic analysis of the cellular response to a potent sensitiser unveils the dynamics of haptenation in living cells. Toxicology. 2020 Dec 1;445:152603. doi: 10.1016/j.tox.2020.152603. Epub 2020 Sep 28.
• [25] Transcriptional signature of human macrophages exposed to the environmental contaminant benzo(a)pyrene. Toxicol Sci. 2010 Apr;114(2):247-59.
• [26] 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.
• [27] 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.
• [28] Transcriptome dynamics of alternative splicing events revealed early phase of apoptosis induced by methylparaben in H1299 human lung carcinoma cells. Arch Toxicol. 2020 Jan;94(1):127-140. doi: 10.1007/s00204-019-02629-w. Epub 2019 Nov 20.
• [29] Molecular mechanisms of quercitrin-induced apoptosis in non-small cell lung cancer. Arch Med Res. 2014 Aug;45(6):445-54.
• [30] 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.