Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTS5EVHH)

• DOT Name: Chromodomain-helicase-DNA-binding protein 5 (CHD5)
• Synonyms: CHD-5; EC 3.6.4.12; ATP-dependent helicase CHD5
• Gene Name: CHD5
• Related Disease:
  Intellectual disability
  Adenoma
  Advanced cancer
  Bladder cancer
  Breast cancer
  Breast carcinoma
  Carcinoma
  Clear cell renal carcinoma
  Cutaneous melanoma
  Endometriosis
  Epithelial ovarian cancer
  Gastric cancer
  Glioma
  Head-neck squamous cell carcinoma
  Hepatocellular carcinoma
  leukaemia
  Leukemia
  Lung cancer
  Lung carcinoma
  Melanoma
  Neoplasm
  Neuroblastoma
  Non-small-cell lung cancer
  Ovarian cancer
  Ovarian neoplasm
  Pancreatic adenocarcinoma
  Pancreatic cancer
  Parenti-mignot neurodevelopmental syndrome
  Prostate cancer
  Rectal carcinoma
  Renal cell carcinoma
  Stomach cancer
  Urinary bladder cancer
  Urinary bladder neoplasm
  Laryngeal squamous cell carcinoma
  Colorectal neoplasm
  Adult glioblastoma
  Autism spectrum disorder
  Congenital heart disease
  Gallbladder carcinoma
  Glioblastoma multiforme
  Neuroblastic tumor
  Schizophrenia
• UniProt ID: CHD5_HUMAN
• PDB ID: 6GUU
• EC Number: 3.6.4.12
• Pfam ID: PF08074 ; PF06461 ; PF08073 ; PF00385 ; PF06465 ; PF00271 ; PF00628 ; PF00176
• Sequence:
  MRGPVGTEEELPRLFAEEMENEDEMSEEEDGGLEAFDDFFPVEPVSLPKKKKPKKLKENK
  CKGKRKKKEGSNDELSENEEDLEEKSESEGSDYSPNKKKKKKLKDKKEKKAKRKKKDEDE
  DDNDDGCLKEPKSSGQLMAEWGLDDVDYLFSEEDYHTLTNYKAFSQFLRPLIAKKNPKIP
  MSKMMTVLGAKWREFSANNPFKGSSAAAAAAAVAAAVETVTISPPLAVSPPQVPQPVPIR
  KAKTKEGKGPGVRKKIKGSKDGKKKGKGKKTAGLKFRFGGISNKRKKGSSSEEDEREESD
  FDSASIHSASVRSECSAALGKKSKRRRKKKRIDDGDGYETDHQDYCEVCQQGGEIILCDT
  CPRAYHLVCLDPELEKAPEGKWSCPHCEKEGIQWEPKDDDDEEEEGGCEEEEDDHMEFCR
  VCKDGGELLCCDACPSSYHLHCLNPPLPEIPNGEWLCPRCTCPPLKGKVQRILHWRWTEP
  PAPFMVGLPGPDVEPSLPPPKPLEGIPEREFFVKWAGLSYWHCSWVKELQLELYHTVMYR
  NYQRKNDMDEPPPFDYGSGDEDGKSEKRKNKDPLYAKMEERFYRYGIKPEWMMIHRILNH
  SFDKKGDVHYLIKWKDLPYDQCTWEIDDIDIPYYDNLKQAYWGHRELMLGEDTRLPKRLL
  KKGKKLRDDKQEKPPDTPIVDPTVKFDKQPWYIDSTGGTLHPYQLEGLNWLRFSWAQGTD
  TILADEMGLGKTVQTIVFLYSLYKEGHSKGPYLVSAPLSTIINWEREFEMWAPDFYVVTY
  TGDKESRSVIRENEFSFEDNAIRSGKKVFRMKKEVQIKFHVLLTSYELITIDQAILGSIE
  WACLVVDEAHRLKNNQSKFFRVLNSYKIDYKLLLTGTPLQNNLEELFHLLNFLTPERFNN
  LEGFLEEFADISKEDQIKKLHDLLGPHMLRRLKADVFKNMPAKTELIVRVELSQMQKKYY
  KFILTRNFEALNSKGGGNQVSLLNIMMDLKKCCNHPYLFPVAAVEAPVLPNGSYDGSSLV
  KSSGKLMLLQKMLKKLRDEGHRVLIFSQMTKMLDLLEDFLEYEGYKYERIDGGITGGLRQ
  EAIDRFNAPGAQQFCFLLSTRAGGLGINLATADTVIIYDSDWNPHNDIQAFSRAHRIGQN
  KKVMIYRFVTRASVEERITQVAKRKMMLTHLVVRPGLGSKSGSMTKQELDDILKFGTEEL
  FKDDVEGMMSQGQRPVTPIPDVQSSKGGNLAASAKKKHGSTPPGDNKDVEDSSVIHYDDA
  AISKLLDRNQDATDDTELQNMNEYLSSFKVAQYVVREEDGVEEVEREIIKQEENVDPDYW
  EKLLRHHYEQQQEDLARNLGKGKRIRKQVNYNDASQEDQEWQDELSDNQSEYSIGSEDED
  EDFEERPEGQSGRRQSRRQLKSDRDKPLPPLLARVGGNIEVLGFNARQRKAFLNAIMRWG
  MPPQDAFNSHWLVRDLRGKSEKEFRAYVSLFMRHLCEPGADGAETFADGVPREGLSRQHV
  LTRIGVMSLVRKKVQEFEHVNGKYSTPDLIPEGPEGKKSGEVISSDPNTPVPASPAHLLP
  APLGLPDKMEAQLGYMDEKDPGAQKPRQPLEVQALPAALDRVESEDKHESPASKERAREE
  RPEETEKAPPSPEQLPREEVLPEKEKILDKLELSLIHSRGDSSELRPDDTKAEEKEPIET
  QQNGDKEEDDEGKKEDKKGKFKFMFNIADGGFTELHTLWQNEERAAVSSGKIYDIWHRRH
  DYWLLAGIVTHGYARWQDIQNDPRYMILNEPFKSEVHKGNYLEMKNKFLARRFKLLEQAL
  VIEEQLRRAAYLNMTQDPNHPAMALNARLAEVECLAESHQHLSKESLAGNKPANAVLHKV
  LNQLEELLSDMKADVTRLPSMLSRIPPVAARLQMSERSILSRLTNRAGDPTIQQGAFGSS
  QMYSNNFGPNFRGPGPGGIVNYNQMPLGPYVTDI
• Function: Chromatin-remodeling protein that binds DNA through histones and regulates gene transcription. May specifically recognize and bind trimethylated 'Lys-27' (H3K27me3) and non-methylated 'Lys-4' of histone H3. Acts as a component of the histone deacetylase NuRD complex which participates in the remodeling of chromatin. Plays a role in the development of the nervous system by activating the expression of genes promoting neuron terminal differentiation. In parallel, it may also positively regulate the trimethylation of histone H3 at 'Lys-27' thereby specifically repressing genes that promote the differentiation into non-neuronal cell lineages. Regulates the expression of genes involved in cell proliferation and differentiation. Downstream activated genes may include CDKN2A that positively regulates the p53/TP53 pathway, which in turn, prevents cell proliferation. In spermatogenesis, it probably regulates histone hyperacetylation and the replacement of histones by transition proteins in chromatin, a crucial step in the condensation of spermatid chromatin and the production of functional spermatozoa.
• Tissue Specificity: Preferentially expressed in total brain, fetal brain, and cerebellum. It is also moderately expressed in the adrenal gland and detected in testis.

Molecular Interaction Atlas (MIA) of This DOT

43 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Intellectual disability	DISMBNXP	Definitive	Biomarker	[1]
Adenoma	DIS78ZEV	Strong	Biomarker	[2]
Advanced cancer	DISAT1Z9	Strong	Biomarker	[3]
Bladder cancer	DISUHNM0	Strong	Biomarker	[4]
Breast cancer	DIS7DPX1	Strong	Altered Expression	[5]
Breast carcinoma	DIS2UE88	Strong	Altered Expression	[5]
Carcinoma	DISH9F1N	Strong	Altered Expression	[6]
Clear cell renal carcinoma	DISBXRFJ	Strong	Genetic Variation	[7]
Cutaneous melanoma	DIS3MMH9	Strong	Genetic Variation	[8]
Endometriosis	DISX1AG8	Strong	Genetic Variation	[9]
Epithelial ovarian cancer	DIS56MH2	Strong	Altered Expression	[10]
Gastric cancer	DISXGOUK	Strong	Biomarker	[11]
Glioma	DIS5RPEH	Strong	Biomarker	[12]
Head-neck squamous cell carcinoma	DISF7P24	Strong	Biomarker	[13]
Hepatocellular carcinoma	DIS0J828	Strong	Genetic Variation	[14]
leukaemia	DISS7D1V	Strong	Altered Expression	[15]
Leukemia	DISNAKFL	Strong	Altered Expression	[15]
Lung cancer	DISCM4YA	Strong	Altered Expression	[16]
Lung carcinoma	DISTR26C	Strong	Altered Expression	[16]
Melanoma	DIS1RRCY	Strong	Genetic Variation	[8]
Neoplasm	DISZKGEW	Strong	Genetic Variation	[17]
Neuroblastoma	DISVZBI4	Strong	Altered Expression	[18]
Non-small-cell lung cancer	DIS5Y6R9	Strong	Biomarker	[3]
Ovarian cancer	DISZJHAP	Strong	Altered Expression	[10]
Ovarian neoplasm	DISEAFTY	Strong	Altered Expression	[10]
Pancreatic adenocarcinoma	DISKHX7S	Strong	Altered Expression	[19]
Pancreatic cancer	DISJC981	Strong	Altered Expression	[19]
Parenti-mignot neurodevelopmental syndrome	DISGCD7A	Strong	Autosomal dominant	[20]
Prostate cancer	DISF190Y	Strong	Biomarker	[12]
Rectal carcinoma	DIS8FRR7	Strong	Posttranslational Modification	[21]
Renal cell carcinoma	DISQZ2X8	Strong	Genetic Variation	[7]
Stomach cancer	DISKIJSX	Strong	Biomarker	[11]
Urinary bladder cancer	DISDV4T7	Strong	Biomarker	[4]
Urinary bladder neoplasm	DIS7HACE	Strong	Biomarker	[4]
Laryngeal squamous cell carcinoma	DIS9UUVF	moderate	Posttranslational Modification	[22]
Colorectal neoplasm	DISR1UCN	Disputed	Biomarker	[23]
Adult glioblastoma	DISVP4LU	Limited	Altered Expression	[24]
Autism spectrum disorder	DISXK8NV	Limited	Biomarker	[1]
Congenital heart disease	DISQBA23	Limited	Genetic Variation	[25]
Gallbladder carcinoma	DISD6ACL	Limited	Altered Expression	[26]
Glioblastoma multiforme	DISK8246	Limited	Altered Expression	[24]
Neuroblastic tumor	DISKWPS1	Limited	Altered Expression	[27]
Schizophrenia	DISSRV2N	Limited	Unknown	[28]

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 Chromodomain-helicase-DNA-binding protein 5 (CHD5).	[29]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene increases the methylation of Chromodomain-helicase-DNA-binding protein 5 (CHD5).	[33]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Cisplatin	DMRHGI9	Approved	Cisplatin decreases the expression of Chromodomain-helicase-DNA-binding protein 5 (CHD5).	[30]
Estradiol	DMUNTE3	Approved	Estradiol increases the expression of Chromodomain-helicase-DNA-binding protein 5 (CHD5).	[31]
(+)-JQ1	DM1CZSJ	Phase 1	(+)-JQ1 decreases the expression of Chromodomain-helicase-DNA-binding protein 5 (CHD5).	[34]
Acetaldehyde	DMJFKG4	Investigative	Acetaldehyde increases the expression of Chromodomain-helicase-DNA-binding protein 5 (CHD5).	[35]

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 Chromodomain-helicase-DNA-binding protein 5 (CHD5).	[32]

References

• [1] Regulation of neuronal connectivity in the mammalian brain by chromatin remodeling.Curr Opin Neurobiol. 2019 Dec;59:59-68. doi: 10.1016/j.conb.2019.04.010. Epub 2019 May 28.
• [2] Epigenetic silencing of CHD5, a novel tumor-suppressor gene, occurs in early colorectal cancer stages.Cancer. 2014 Jan 15;120(2):172-80. doi: 10.1002/cncr.28316. Epub 2013 Nov 14.
• [3] CHD5 is a potential tumor suppressor in non small cell lung cancer (NSCLC).Gene. 2017 Jun 30;618:65-68. doi: 10.1016/j.gene.2017.04.010. Epub 2017 Apr 8.
• [4] Novel variants in MLL confer to bladder cancer recurrence identified by whole-exome sequencing.Oncotarget. 2016 Jan 19;7(3):2629-45. doi: 10.18632/oncotarget.6380.
• [5] Chromodomain helicase DNA binding protein 5 plays a tumor suppressor role in human breast cancer.Breast Cancer Res. 2012 May 8;14(3):R73. doi: 10.1186/bcr3182.
• [6] Distinct high-profile methylated genes in colorectal cancer.PLoS One. 2009 Sep 11;4(9):e7012. doi: 10.1371/journal.pone.0007012.
• [7] The epigenetic modifier CHD5 functions as a novel tumor suppressor for renal cell carcinoma and is predominantly inactivated by promoter CpG methylation.Oncotarget. 2016 Apr 19;7(16):21618-30. doi: 10.18632/oncotarget.7822.
• [8] Preliminary evidence for involvement of the tumour suppressor gene CHD5 in a family with cutaneous melanoma.Br J Dermatol. 2011 May;164(5):1010-6. doi: 10.1111/j.1365-2133.2011.10223.x.
• [9] Analysis of common variations in tumor-suppressor genes on chr1p36 among Caucasian women with endometriosis.Gynecol Oncol. 2012 Nov;127(2):398-402. doi: 10.1016/j.ygyno.2012.08.013. Epub 2012 Aug 19.
• [10] CHD5 Downregulation Associated with Poor Prognosis in Epithelial Ovarian Cancer.Gynecol Obstet Invest. 2011;72(3):203-7. doi: 10.1159/000323883. Epub 2011 Aug 23.
• [11] CHD5 is down-regulated through promoter hypermethylation in gastric cancer.J Biomed Sci. 2009 Oct 19;16(1):95. doi: 10.1186/1423-0127-16-95.
• [12] Role of CHD5 in human cancers: 10 years later.Cancer Res. 2014 Feb 1;74(3):652-8. doi: 10.1158/0008-5472.CAN-13-3056. Epub 2014 Jan 13.
• [13] miRNA-24-3p promotes cell proliferation and regulates chemosensitivity in head and neck squamous cell carcinoma by targeting CHD5.Future Oncol. 2016 Dec;12(23):2701-2712. doi: 10.2217/fon-2016-0179. Epub 2016 Aug 11.
• [14] A rare CHD5 haplotype and its interactions with environmental factors predicting hepatocellular carcinoma risk.BMC Cancer. 2018 Jun 15;18(1):658. doi: 10.1186/s12885-018-4551-y.
• [15] Silencing of CHD5 gene by promoter methylation in leukemia.PLoS One. 2014 Jan 13;9(1):e85172. doi: 10.1371/journal.pone.0085172. eCollection 2014.
• [16] CHD5, a tumor suppressor that is epigenetically silenced in lung cancer.Lung Cancer. 2012 Jun;76(3):324-31. doi: 10.1016/j.lungcan.2011.11.019. Epub 2011 Dec 18.
• [17] rs187960998 polymorphism in miR-211 prevents development of human colon cancer by deregulation of 3'UTR in CHD5.Onco Targets Ther. 2019 Jan 3;12:405-412. doi: 10.2147/OTT.S180935. eCollection 2019.
• [18] Role of microRNAs in epigenetic silencing of the CHD5 tumor suppressor gene in neuroblastomas.Oncotarget. 2016 Mar 29;7(13):15977-85. doi: 10.18632/oncotarget.7434.
• [19] Low CHD5 expression activates the DNA damage response and predicts poor outcome in patients undergoing adjuvant therapy for resected pancreatic cancer.Oncogene. 2014 Nov 20;33(47):5450-6. doi: 10.1038/onc.2013.488. Epub 2013 Nov 25.
• [20] Missense and truncating variants in CHD5 in a dominant neurodevelopmental disorder with intellectual disability, behavioral disturbances, and epilepsy. Hum Genet. 2021 Jul;140(7):1109-1120. doi: 10.1007/s00439-021-02283-2. Epub 2021 May 4.
• [21] Influence of colorectal cancer tumor suppressor gene CHD5 methylation on its clinical and pathological characteristics.J Biol Regul Homeost Agents. 2015 Oct-Dec;29(4):889-93.
• [22] The involvement of CHD5 hypermethylation in laryngeal squamous cell carcinoma.Oral Oncol. 2011 Jul;47(7):601-8. doi: 10.1016/j.oraloncology.2011.05.003. Epub 2011 Jun 1.
• [23] Genomic and epigenomic integration identifies a prognostic signature in colon cancer.Clin Cancer Res. 2011 Mar 15;17(6):1535-45. doi: 10.1158/1078-0432.CCR-10-2509. Epub 2011 Jan 28.
• [24] MiR?00a?p promotes glioblastoma cell proliferation, migration and invasion by targeting chromodomain helicase DNA binding protein 5.Mol Med Rep. 2018 Sep;18(3):2689-2696. doi: 10.3892/mmr.2018.9259. Epub 2018 Jul 9.
• [25] Expression of the congenital heart disease 5/tryptophan rich basic protein homologue gene during heart development in medaka fish, Oryzias latipes.Dev Growth Differ. 2009 Feb;51(2):95-107. doi: 10.1111/j.1440-169X.2008.01084.x.
• [26] Decreased expression of chromodomain helicase DNA-binding protein 5 is an unfavorable prognostic marker in patients with primary gallbladder carcinoma.Clin Transl Oncol. 2013 Mar;15(3):198-204. doi: 10.1007/s12094-012-0903-2. Epub 2012 Jul 24.
• [27] Expression of the neuron-specific protein CHD5 is an independent marker of outcome in neuroblastoma.Mol Cancer. 2010 Oct 15;9:277. doi: 10.1186/1476-4598-9-277.
• [28] Exome sequencing in 53 sporadic cases of schizophrenia identifies 18 putative candidate genes. PLoS One. 2014 Nov 24;9(11):e112745. doi: 10.1371/journal.pone.0112745. eCollection 2014.
• [29] 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.
• [30] Activation of AIFM2 enhances apoptosis of human lung cancer cells undergoing toxicological stress. Toxicol Lett. 2016 Sep 6;258:227-236.
• [31] 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.
• [32] 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.
• [33] 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.
• [34] CCAT1 is an enhancer-templated RNA that predicts BET sensitivity in colorectal cancer. J Clin Invest. 2016 Feb;126(2):639-52.
• [35] Transcriptome profile analysis of saturated aliphatic aldehydes reveals carbon number-specific molecules involved in pulmonary toxicity. Chem Res Toxicol. 2014 Aug 18;27(8):1362-70.