Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTU1GB68)

• DOT Name: PR domain zinc finger protein 5 (PRDM5)
• Synonyms: EC 2.1.1.-; PR domain-containing protein 5
• Gene Name: PRDM5
• Related Disease:
  Brittle cornea syndrome 2
  Cervical cancer
  Cervical carcinoma
  OPTN-related open angle glaucoma
  Acute myelogenous leukaemia
  Adenoma
  Axenfeld-Rieger syndrome
  Connective tissue disorder
  Crohn disease
  Epithelial ovarian cancer
  Hepatocellular carcinoma
  Intrahepatic cholangiocarcinoma
  Keratoconus
  Lung cancer
  Lung carcinoma
  Lung squamous cell carcinoma
  Polyp
  Neoplasm
  Brittle cornea syndrome
  Advanced cancer
  Digestive system neoplasm
• UniProt ID: PRDM5_HUMAN
• PDB ID: 6XAZ
• EC Number: 2.1.1.-
• Pfam ID: PF21549 ; PF00096 ; PF13912 ; PF12874
• Sequence:
  MLGMYVPDRFSLKSSRVQDGMGLYTARRVRKGEKFGPFAGEKRMPEDLDENMDYRLMWEV
  RGSKGEVLYILDATNPRHSNWLRFVHEAPSQEQKNLAAIQEGENIFYLAVEDIETDTELL
  IGYLDSDMEAEEEEQQIMTVIKEGEVENSRRQSTAGRKDRLGCKEDYACPQCESSFTSED
  ILAEHLQTLHQKPTEEKEFKCKNCGKKFPVKQALQRHVLQCTAKSSLKESSRSFQCSVCN
  SSFSSASSFEQHQETCRGDARFVCKADSCGKRLKSKDALKRHQENVHTGDPKKKLICSVC
  NKKCSSASSLQEHRKIHEIFDCQECMKKFISANQLKRHMITHSEKRPYNCEICNKSFKRL
  DQVGAHKVIHSEDKPYKCKLCGKGFAHRNVYKNHKKTHSEERPFQCEECKALFRTPFSLQ
  RHLLIHNSERTFKCHHCDATFKRKDTLNVHVQVVHERHKKYRCELCNKAFVTPSVLRSHK
  KTHTGEKEKICPYCGQKFASSGTLRVHIRSHTGERPYQCPYCEKGFSKNDGLKMHIRTHT
  REKPYKCSECSKAFSQKRGLDEHKRTHTGEKPFQCDVCDLAFSLKKMLIRHKMTHNPNRP
  LAECQFCHKKFTRNDYLKVHMDNIHGVADS
• Function: Sequence-specific DNA-binding transcription factor. Represses transcription at least in part by recruitment of the histone methyltransferase EHMT2/G9A and histone deacetylases such as HDAC1. Regulates hematopoiesis-associated protein-coding and microRNA (miRNA) genes. May regulate the expression of proteins involved in extracellular matrix development and maintenance, including fibrillar collagens, such as COL4A1 and COL11A1, connective tissue components, such as HAPLN1, and molecules regulating cell migration and adhesion, including EDIL3 and TGFB2. May cause G2/M arrest and apoptosis in cancer cells.
• Tissue Specificity: Widely expressed with highest levels in colon and ovary. Tends to be silenced in breast, colorectal, gastric and liver cancer tissues.

Molecular Interaction Atlas (MIA) of This DOT

21 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Brittle cornea syndrome 2	DISDYP5V	Definitive	Autosomal recessive	[1]
Cervical cancer	DISFSHPF	Definitive	Altered Expression	[2]
Cervical carcinoma	DIST4S00	Definitive	Altered Expression	[2]
OPTN-related open angle glaucoma	DISDR98A	Definitive	Biomarker	[3]
Acute myelogenous leukaemia	DISCSPTN	Strong	Biomarker	[4]
Adenoma	DIS78ZEV	Strong	Genetic Variation	[5]
Axenfeld-Rieger syndrome	DIS6XY4L	Strong	Genetic Variation	[6]
Connective tissue disorder	DISKXBS3	Strong	Genetic Variation	[7]
Crohn disease	DIS2C5Q8	Strong	Altered Expression	[8]
Epithelial ovarian cancer	DIS56MH2	Strong	Genetic Variation	[9]
Hepatocellular carcinoma	DIS0J828	Strong	Posttranslational Modification	[10]
Intrahepatic cholangiocarcinoma	DIS6GOC8	Strong	Biomarker	[11]
Keratoconus	DISOONXH	Strong	Genetic Variation	[6]
Lung cancer	DISCM4YA	Strong	Biomarker	[12]
Lung carcinoma	DISTR26C	Strong	Biomarker	[12]
Lung squamous cell carcinoma	DISXPIBD	Strong	Biomarker	[12]
Polyp	DISRSLYF	Strong	Genetic Variation	[5]
Neoplasm	DISZKGEW	moderate	Posttranslational Modification	[4]
Brittle cornea syndrome	DIS2L5YZ	Supportive	Autosomal recessive	[13]
Advanced cancer	DISAT1Z9	Limited	Altered Expression	[14]
Digestive system neoplasm	DISPOJCT	Limited	Genetic Variation	[15]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Valproate	DMCFE9I	Approved	Valproate decreases the expression of PR domain zinc finger protein 5 (PRDM5).	[16]
Cupric Sulfate	DMP0NFQ	Approved	Cupric Sulfate decreases the expression of PR domain zinc finger protein 5 (PRDM5).	[17]
SNDX-275	DMH7W9X	Phase 3	SNDX-275 decreases the expression of PR domain zinc finger protein 5 (PRDM5).	[18]
GALLICACID	DM6Y3A0	Investigative	GALLICACID increases the expression of PR domain zinc finger protein 5 (PRDM5).	[20]
cinnamaldehyde	DMZDUXG	Investigative	cinnamaldehyde increases the expression of PR domain zinc finger protein 5 (PRDM5).	[21]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene affects the methylation of PR domain zinc finger protein 5 (PRDM5).	[19]

References

• [1] Identification of Mutations in the PRDM5 Gene in Brittle Cornea Syndrome. Cornea. 2016 Jun;35(6):853-9. doi: 10.1097/ICO.0000000000000824.
• [2] DNA methylation and carcinogenesis of PRDM5 in cervical cancer.J Cancer Res Clin Oncol. 2010 Dec;136(12):1821-5. doi: 10.1007/s00432-010-0840-9. Epub 2010 Mar 6.
• [3] Genetic factors influencing the reduction of central corneal thickness in disorders affecting the eye.Ophthalmic Genet. 2017 Dec;38(6):501-510. doi: 10.1080/13816810.2017.1313993. Epub 2017 Apr 28.
• [4] Overexpression of PRDM5 promotes acute myeloid leukemia cell proliferation and migration by activating the JNK pathway.Cancer Med. 2019 Jul;8(8):3905-3917. doi: 10.1002/cam4.2261. Epub 2019 May 23.
• [5] Methylation and expression of the tumour suppressor, PRDM5, in colorectal cancer and polyp subgroups.BMC Cancer. 2015 Jan 23;15:20. doi: 10.1186/s12885-015-1011-9.
• [6] Whole exome sequencing identifies a heterozygous missense variant in the PRDM5 gene in a family with Axenfeld-Rieger syndrome.Neurogenetics. 2016 Jan;17(1):17-23. doi: 10.1007/s10048-015-0462-0. Epub 2015 Oct 21.
• [7] A role for repressive complexes and H3K9 di-methylation in PRDM5-associated brittle cornea syndrome.Hum Mol Genet. 2015 Dec 1;24(23):6565-79. doi: 10.1093/hmg/ddv345. Epub 2015 Sep 22.
• [8] PRDM5 promotes the apoptosis of epithelial cells induced by IFN- during Crohn's disease.Pathol Res Pract. 2017 Jun;213(6):666-673. doi: 10.1016/j.prp.2016.12.004. Epub 2016 Dec 5.
• [9] Molecular bases of aberrant miR-182 expression in ovarian cancer.Genes Chromosomes Cancer. 2016 Nov;55(11):877-89. doi: 10.1002/gcc.22387. Epub 2016 Jul 12.
• [10] The epigenetic modifier PRDM5 functions as a tumor suppressor through modulating WNT/-catenin signaling and is frequently silenced in multiple tumors.PLoS One. 2011;6(11):e27346. doi: 10.1371/journal.pone.0027346. Epub 2011 Nov 8.
• [11] Necroptosis microenvironment directs lineage commitment in liver cancer.Nature. 2018 Oct;562(7725):69-75. doi: 10.1038/s41586-018-0519-y. Epub 2018 Sep 12.
• [12] Promoter methylation-mediated downregulation of PRDM5 contributes to the development of lung squamous cell carcinoma.Tumour Biol. 2014 May;35(5):4509-16. doi: 10.1007/s13277-013-1593-2. Epub 2014 Jan 7.
• [13] Mutations in PRDM5 in brittle cornea syndrome identify a pathway regulating extracellular matrix development and maintenance. Am J Hum Genet. 2011 Jun 10;88(6):767-777. doi: 10.1016/j.ajhg.2011.05.007.
• [14] DNA methylation accumulation in gastric mucosa adjacent to cancer after Helicobacter pylori eradication.Int J Cancer. 2019 Jan 1;144(1):80-88. doi: 10.1002/ijc.31667. Epub 2018 Nov 12.
• [15] PRDM5 identified as a target of epigenetic silencing in colorectal and gastric cancer.Clin Cancer Res. 2007 Aug 15;13(16):4786-94. doi: 10.1158/1078-0432.CCR-07-0305.
• [16] Human embryonic stem cell-derived test systems for developmental neurotoxicity: a transcriptomics approach. Arch Toxicol. 2013 Jan;87(1):123-43.
• [17] Physiological and toxicological transcriptome changes in HepG2 cells exposed to copper. Physiol Genomics. 2009 Aug 7;38(3):386-401.
• [18] 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.
• [19] 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.
• [20] 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.
• [21] Comparative DNA microarray analysis of human monocyte derived dendritic cells and MUTZ-3 cells exposed to the moderate skin sensitizer cinnamaldehyde. Toxicol Appl Pharmacol. 2009 Sep 15;239(3):273-83.