Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTRAD2TT)

• DOT Name: E3 ubiquitin-protein ligase CHFR (CHFR)
• Synonyms: EC 2.3.2.27; Checkpoint with forkhead and RING finger domains protein; RING finger protein 196; RING-type E3 ubiquitin transferase CHFR
• Gene Name: CHFR
• Related Disease:
  Acute myelogenous leukaemia
  Carcinoma of esophagus
  Esophageal cancer
  Lung cancer
  Lung carcinoma
  Neoplasm of esophagus
  Adenocarcinoma
  Advanced cancer
  Breast cancer
  Breast carcinoma
  Breast neoplasm
  Carcinoma
  Cervical cancer
  Cervical carcinoma
  Colon carcinoma
  Colorectal carcinoma
  Colorectal neoplasm
  Endometrial carcinoma
  Epithelial ovarian cancer
  Familial adenomatous polyposis
  Gastric cancer
  Lung neoplasm
  Lung squamous cell carcinoma
  Myelodysplastic syndrome
  Nasopharyngeal carcinoma
  Oropharyngeal squamous cell carcinoma
  Ovarian cancer
  Ovarian neoplasm
  Squamous cell carcinoma
  Stomach cancer
  Colon cancer
  Endometrial cancer
  Endometrium neoplasm
  Gastric neoplasm
  Hereditary diffuse gastric adenocarcinoma
  Primary cutaneous T-cell lymphoma
  Thyroid gland papillary carcinoma
• UniProt ID: CHFR_HUMAN
• PDB ID: 1LGP; 1LGQ; 2XOC; 2XOY; 2XOZ; 2XP0
• EC Number: 2.3.2.27
• Pfam ID: PF00498 ; PF13923 ; PF17979
• Sequence:
  MERPEEGKQSPPPQPWGRLLRLGAEEGEPHVLLRKREWTIGRRRGCDLSFPSNKLVSGDH
  CRIVVDEKSGQVTLEDTSTSGTVINKLKVVKKQTCPLQTGDVIYLVYRKNEPEHNVAYLY
  ESLSEKQGMTQESFEANKENVFHGTKDTSGAGAGRGADPRVPPSSPATQVCFEEPQPSTS
  TSDLFPTASASSTEPSPAGRERSSSCGSGGGGISPKGSGPSVASDEVSSFASALPDRKTA
  SFSSLEPQDQEDLEPVKKKMRGDGDLDLNGQLLVAQPRRNAQTVHEDVRAAAGKPDKMEE
  TLTCIICQDLLHDCVSLQPCMHTFCAACYSGWMERSSLCPTCRCPVERICKNHILNNLVE
  AYLIQHPDKSRSEEDVQSMDARNKITQDMLQPKVRRSFSDEEGSSEDLLELSDVDSESSD
  ISQPYVVCRQCPEYRRQAAQPPHCPAPEGEPGAPQALGDAPSTSVSLTTAVQDYVCPLQG
  SHALCTCCFQPMPDRRAEREQDPRVAPQQCAVCLQPFCHLYWGCTRTGCYGCLAPFCELN
  LGDKCLDGVLNNNSYESDILKNYLATRGLTWKNMLTESLVALQRGVFLLSDYRVTGDTVL
  CYCCGLRSFRELTYQYRQNIPASELPVAVTSRPDCYWGRNCRTQVKAHHAMKFNHICEQT
  RFKN
• Function: E3 ubiquitin-protein ligase that functions in the antephase checkpoint by actively delaying passage into mitosis in response to microtubule poisons. Acts in early prophase before chromosome condensation, when the centrosome move apart from each other along the periphery of the nucleus. Probably involved in signaling the presence of mitotic stress caused by microtubule poisons by mediating the 'Lys-48'-linked ubiquitination of target proteins, leading to their degradation by the proteasome. Promotes the ubiquitination and subsequent degradation of AURKA and PLK1. Probably acts as a tumor suppressor, possibly by mediating the polyubiquitination of HDAC1, leading to its degradation. May also promote the formation of 'Lys-63'-linked polyubiquitin chains and functions with the specific ubiquitin-conjugating UBC13-MMS2 (UBE2N-UBE2V2) heterodimer. Substrates that are polyubiquitinated at 'Lys-63' are usually not targeted for degradation, but are rather involved in signaling cellular stress.
• Tissue Specificity: Ubiquitous.

Molecular Interaction Atlas (MIA) of This DOT

37 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Acute myelogenous leukaemia	DISCSPTN	Definitive	Altered Expression	[1]
Carcinoma of esophagus	DISS6G4D	Definitive	Altered Expression	[2]
Esophageal cancer	DISGB2VN	Definitive	Altered Expression	[2]
Lung cancer	DISCM4YA	Definitive	Altered Expression	[3]
Lung carcinoma	DISTR26C	Definitive	Altered Expression	[3]
Neoplasm of esophagus	DISOLKAQ	Definitive	Altered Expression	[2]
Adenocarcinoma	DIS3IHTY	Strong	Altered Expression	[3]
Advanced cancer	DISAT1Z9	Strong	Biomarker	[4]
Breast cancer	DIS7DPX1	Strong	Altered Expression	[5]
Breast carcinoma	DIS2UE88	Strong	Altered Expression	[5]
Breast neoplasm	DISNGJLM	Strong	Biomarker	[6]
Carcinoma	DISH9F1N	Strong	Posttranslational Modification	[7]
Cervical cancer	DISFSHPF	Strong	Biomarker	[8]
Cervical carcinoma	DIST4S00	Strong	Biomarker	[8]
Colon carcinoma	DISJYKUO	Strong	Posttranslational Modification	[9]
Colorectal carcinoma	DIS5PYL0	Strong	Posttranslational Modification	[10]
Colorectal neoplasm	DISR1UCN	Strong	Genetic Variation	[11]
Endometrial carcinoma	DISXR5CY	Strong	Biomarker	[12]
Epithelial ovarian cancer	DIS56MH2	Strong	Biomarker	[13]
Familial adenomatous polyposis	DISW53RE	Strong	Genetic Variation	[10]
Gastric cancer	DISXGOUK	Strong	Posttranslational Modification	[14]
Lung neoplasm	DISVARNB	Strong	Altered Expression	[15]
Lung squamous cell carcinoma	DISXPIBD	Strong	Altered Expression	[16]
Myelodysplastic syndrome	DISYHNUI	Strong	Biomarker	[1]
Nasopharyngeal carcinoma	DISAOTQ0	Strong	Biomarker	[17]
Oropharyngeal squamous cell carcinoma	DIS7D7QV	Strong	Biomarker	[18]
Ovarian cancer	DISZJHAP	Strong	Biomarker	[13]
Ovarian neoplasm	DISEAFTY	Strong	Biomarker	[13]
Squamous cell carcinoma	DISQVIFL	Strong	Genetic Variation	[3]
Stomach cancer	DISKIJSX	Strong	Biomarker	[4]
Colon cancer	DISVC52G	Limited	Posttranslational Modification	[9]
Endometrial cancer	DISW0LMR	Limited	Biomarker	[12]
Endometrium neoplasm	DIS6OS2L	Limited	Biomarker	[19]
Gastric neoplasm	DISOKN4Y	Limited	Posttranslational Modification	[20]
Hereditary diffuse gastric adenocarcinoma	DISUIBYS	Limited	Biomarker	[21]
Primary cutaneous T-cell lymphoma	DIS35WVW	Limited	Biomarker	[22]
Thyroid gland papillary carcinoma	DIS48YMM	Limited	Biomarker	[23]

This DOT Affected the Drug Response of 3 Drug(s)

Drug Name	Drug ID	Highest Status	Interaction	REF
Acetaminophen	DMUIE76	Approved	E3 ubiquitin-protein ligase CHFR (CHFR) affects the response to substance of Acetaminophen.	[33]
Paclitaxel	DMLB81S	Approved	E3 ubiquitin-protein ligase CHFR (CHFR) decreases the response to substance of Paclitaxel.	[8]
Docetaxel	DMDI269	Approved	E3 ubiquitin-protein ligase CHFR (CHFR) decreases the response to substance of Docetaxel.	[8]

6 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 E3 ubiquitin-protein ligase CHFR (CHFR).	[24]
Cupric Sulfate	DMP0NFQ	Approved	Cupric Sulfate increases the expression of E3 ubiquitin-protein ligase CHFR (CHFR).	[25]
Temozolomide	DMKECZD	Approved	Temozolomide increases the expression of E3 ubiquitin-protein ligase CHFR (CHFR).	[27]
Methotrexate	DM2TEOL	Approved	Methotrexate decreases the expression of E3 ubiquitin-protein ligase CHFR (CHFR).	[28]
Decitabine	DMQL8XJ	Approved	Decitabine increases the expression of E3 ubiquitin-protein ligase CHFR (CHFR).	[21]
Bortezomib	DMNO38U	Approved	Bortezomib decreases the expression of E3 ubiquitin-protein ligase CHFR (CHFR).	[30]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Arsenic	DMTL2Y1	Approved	Arsenic affects the methylation of E3 ubiquitin-protein ligase CHFR (CHFR).	[26]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene affects the methylation of E3 ubiquitin-protein ligase CHFR (CHFR).	[31]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A decreases the methylation of E3 ubiquitin-protein ligase CHFR (CHFR).	[32]

References

• [1] Methylation-independent CHFR expression is a potential biomarker affecting prognosis in acute myeloid leukemia.J Cell Physiol. 2018 Jun;233(6):4707-4714. doi: 10.1002/jcp.26253. Epub 2018 Jan 15.
• [2] Chfr expression is downregulated by CpG island hypermethylation in esophageal cancer.Carcinogenesis. 2002 Oct;23(10):1695-9. doi: 10.1093/carcin/23.10.1695.
• [3] Molecular characteristics of non-small cell lung cancer with reduced CHFR expression in The Cancer Genome Atlas (TCGA) project.Respir Med. 2015 Jan;109(1):131-6. doi: 10.1016/j.rmed.2014.11.004. Epub 2014 Nov 21.
• [4] Silencing of CHFR Sensitizes Gastric Carcinoma to PARP Inhibitor Treatment.Transl Oncol. 2020 Jan;13(1):113-121. doi: 10.1016/j.tranon.2019.10.004. Epub 2019 Dec 4.
• [5] Poly(ADPribose) polymerase 1/2 inhibitors decrease the ubiquitination of ALC1 mediated by CHFR in breast cancer.Oncol Rep. 2019 Oct;42(4):1467-1474. doi: 10.3892/or.2019.7242. Epub 2019 Jul 18.
• [6] Altered expression of the early mitotic checkpoint protein, CHFR, in breast cancers: implications for tumor suppression.Cancer Res. 2007 Jul 1;67(13):6064-74. doi: 10.1158/0008-5472.CAN-06-4109. Epub 2007 Jun 27.
• [7] Aberrant methylation of the CHFR gene in digestive tract cancer.Anticancer Res. 2006 May-Jun;26(3A):1791-5.
• [8] Epigenetic inactivation of the CHFR gene in cervical cancer contributes to sensitivity to taxanes. Int J Oncol. 2007 Oct;31(4):713-20.
• [9] Association of CHFR promoter methylation with disease recurrence in locally advanced colon cancer.Clin Cancer Res. 2011 Jul 1;17(13):4531-40. doi: 10.1158/1078-0432.CCR-10-0763. Epub 2011 May 6.
• [10] Phase II study of nab-paclitaxel in refractory small bowel adenocarcinoma and CpG island methylator phenotype (CIMP)-high colorectal cancer.Ann Oncol. 2018 Jan 1;29(1):139-144. doi: 10.1093/annonc/mdx688.
• [11] Coding region polymorphisms in the CHFR mitotic stress checkpoint gene are associated with colorectal cancer risk.Cancer Lett. 2008 Feb 18;260(1-2):170-9. doi: 10.1016/j.canlet.2007.10.036.
• [12] RNA interference targeting CHFR enhances taxol chemosensitivity in endometrial cancer cells.Oncol Rep. 2012 Jul;28(1):248-54. doi: 10.3892/or.2012.1752. Epub 2012 Apr 2.
• [13] The inhibition of UBC13 expression and blockage of the DNMT1-CHFR-Aurora A pathway contribute to paclitaxel resistance in ovarian cancer.Cell Death Dis. 2018 Jan 24;9(2):93. doi: 10.1038/s41419-017-0137-x.
• [14] Predictive value of CHFR and MLH1 methylation in human gastric cancer.Gastric Cancer. 2015 Apr;18(2):280-7. doi: 10.1007/s10120-014-0370-2. Epub 2014 Apr 21.
• [15] First-line therapy and methylation status of CHFR in serum influence outcome to chemotherapy versus EGFR tyrosine kinase inhibitors as second-line therapy in stage IV non-small-cell lung cancer patients.Lung Cancer. 2011 Apr;72(1):84-91. doi: 10.1016/j.lungcan.2010.07.008. Epub 2010 Aug 11.
• [16] CHFR expression is preferentially impaired in smoking-related squamous cell carcinoma of the lung, and the diminished expression significantly harms outcomes.Int J Cancer. 2008 Oct 1;123(7):1623-30. doi: 10.1002/ijc.23673.
• [17] PARP1 is overexpressed in nasopharyngeal carcinoma and its inhibition enhances radiotherapy.Mol Cancer Ther. 2013 Nov;12(11):2517-28. doi: 10.1158/1535-7163.MCT-13-0010. Epub 2013 Aug 26.
• [18] HPV-positive oropharyngeal squamous cell carcinoma is associated with TIMP3 and CADM1 promoter hypermethylation.Cancer Med. 2014 Oct;3(5):1185-96. doi: 10.1002/cam4.313. Epub 2014 Jul 26.
• [19] Relationship of aberrant DNA hypermethylation of CHFR with sensitivity to taxanes in endometrial cancer.Oncol Rep. 2007 Jan;17(1):41-8.
• [20] Mechanism and pathobiologic implications of CHFR promoter methylation in gastric carcinoma.World J Gastroenterol. 2008 Aug 28;14(32):5000-7. doi: 10.3748/wjg.14.5000.
• [21] Chemical genomic screening for methylation-silenced genes in gastric cancer cell lines using 5-aza-2'-deoxycytidine treatment and oligonucleotide microarray. Cancer Sci. 2006 Jan;97(1):64-71.
• [22] Epigenetic profiling of cutaneous T-cell lymphoma: promoter hypermethylation of multiple tumor suppressor genes including BCL7a, PTPRG, and p73.J Clin Oncol. 2005 Jun 10;23(17):3886-96. doi: 10.1200/JCO.2005.11.353. Epub 2005 May 16.
• [23] Identification of epistatic interactions through genome-wide association studies in sporadic medullary and juvenile papillary thyroid carcinomas.BMC Med Genomics. 2015 Dec 21;8:83. doi: 10.1186/s12920-015-0160-7.
• [24] Integrating multiple omics to unravel mechanisms of Cyclosporin A induced hepatotoxicity in vitro. Toxicol In Vitro. 2015 Apr;29(3):489-501.
• [25] Physiological and toxicological transcriptome changes in HepG2 cells exposed to copper. Physiol Genomics. 2009 Aug 7;38(3):386-401.
• [26] 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.
• [27] 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.
• [28] Global molecular effects of tocilizumab therapy in rheumatoid arthritis synovium. Arthritis Rheumatol. 2014 Jan;66(1):15-23.
• [29] Chemical genomic screening for methylation-silenced genes in gastric cancer cell lines using 5-aza-2'-deoxycytidine treatment and oligonucleotide microarray. Cancer Sci. 2006 Jan;97(1):64-71.
• [30] The proapoptotic effect of zoledronic acid is independent of either the bone microenvironment or the intrinsic resistance to bortezomib of myeloma cells and is enhanced by the combination with arsenic trioxide. Exp Hematol. 2011 Jan;39(1):55-65.
• [31] 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.
• [32] 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.
• [33] Interindividual variation in gene expression responses and metabolite formation in acetaminophen-exposed primary human hepatocytes. Arch Toxicol. 2016 May;90(5):1103-15. doi: 10.1007/s00204-015-1545-2. Epub 2015 Jun 24.
• [34] Epigenetic inactivation of the CHFR gene in cervical cancer contributes to sensitivity to taxanes. Int J Oncol. 2007 Oct;31(4):713-20.