Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTWZKY4L)

• DOT Name: PR domain zinc finger protein 14 (PRDM14)
• Synonyms: EC 2.1.1.-; PR domain-containing protein 14
• Gene Name: PRDM14
• Related Disease:
  Advanced cancer
  Cervical cancer
  Chronic pancreatitis
  Colorectal carcinoma
  Germ cell tumor
  leukaemia
  Leukemia
  Lung cancer
  Matthew-Wood syndrome
  Neoplasm
  Neoplasm of testis
  Non-small-cell lung cancer
  Pancreatitis
  Schizophrenia
  Seminoma
  T-cell acute lymphoblastic leukaemia
  Teratoma
  Testicular germ cell tumor
  Triple negative breast cancer
  Breast cancer
  Breast carcinoma
  Childhood acute lymphoblastic leukemia
  Pancreatic cancer
• UniProt ID: PRD14_HUMAN
• EC Number: 2.1.1.-
• Pfam ID: PF21549 ; PF00096
• Sequence:
  MALPRPSEAVPQDKVCYPPESSPQNLAAYYTPFPSYGHYRNSLATVEEDFQPFRQLEAAA
  SAAPAMPPFPFRMAPPLLSPGLGLQREPLYDLPWYSKLPPWYPIPHVPREVPPFLSSSHE
  YAGASSEDLGHQIIGGDNESGPCCGPDTLIPPPPADASLLPEGLRTSQLLPCSPSKQSED
  GPKPSNQEGKSPARFQFTEEDLHFVLYGVTPSLEHPASLHHAISGLLVPPDSSGSDSLPQ
  TLDKDSLQLPEGLCLMQTVFGEVPHFGVFCSSFIAKGVRFGPFQGKVVNASEVKTYGDNS
  VMWEIFEDGHLSHFIDGKGGTGNWMSYVNCARFPKEQNLVAVQCQGHIFYESCKEIHQNQ
  ELLVWYGDCYEKFLDIPVSLQVTEPGKQPSGPSEESAEGYRCERCGKVFTYKYYRDKHLK
  YTPCVDKGDRKFPCSLCKRSFEKRDRLRIHILHVHEKHRPHKCSTCGKCFSQSSSLNKHM
  RVHSGDRPYQCVYCTKRFTASSILRTHIRQHSGEKPFKCKYCGKSFASHAAHDSHVRRSH
  KEDDGCSCSICGKIFSDQETFYSHMKFHEDY
• Function: Transcription factor that has both positive and negative roles on transcription. Required for the maintenance of embryonic stem cell identity and the reacquisition of pluripotency in somatic cells. May play an essential role in germ cell development at 2 levels: the reacquisition of potential pluripotency, including SOX2 up-regulation, and successful epigenetic reprogramming, characterized by EHMT1 repression. Its association with CBFA2T2 is required for the functions in pluripotency and germ cell formation. Directly up-regulates the expression of pluripotency gene POU5F1 through its proximal enhancer. Binds to the DNA consensus sequence 5'-GGTC[TC]CTAA-3'.
• Tissue Specificity: Expressed in embryonic stem cells. Tends to be overexpressed in breast cancer (at protein level).
• Reactome Pathway: Transcriptional regulation of pluripotent stem cells (R-HSA-452723)

Molecular Interaction Atlas (MIA) of This DOT

23 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Advanced cancer	DISAT1Z9	Strong	Biomarker	[1]
Cervical cancer	DISFSHPF	Strong	Altered Expression	[2]
Chronic pancreatitis	DISBUOMJ	Strong	Biomarker	[3]
Colorectal carcinoma	DIS5PYL0	Strong	Altered Expression	[4]
Germ cell tumor	DIS62070	Strong	Altered Expression	[5]
leukaemia	DISS7D1V	Strong	Biomarker	[1]
Leukemia	DISNAKFL	Strong	Biomarker	[1]
Lung cancer	DISCM4YA	Strong	Biomarker	[6]
Matthew-Wood syndrome	DISA7HR7	Strong	Altered Expression	[3]
Neoplasm	DISZKGEW	Strong	Biomarker	[4]
Neoplasm of testis	DISK4XHT	Strong	Genetic Variation	[7]
Non-small-cell lung cancer	DIS5Y6R9	Strong	Biomarker	[8]
Pancreatitis	DIS0IJEF	Strong	Altered Expression	[3]
Schizophrenia	DISSRV2N	Strong	Genetic Variation	[9]
Seminoma	DIS3J8LJ	Strong	Biomarker	[5]
T-cell acute lymphoblastic leukaemia	DIS17AI2	Strong	Biomarker	[1]
Teratoma	DIS6ICY4	Strong	Altered Expression	[5]
Testicular germ cell tumor	DIS5RN24	Strong	Genetic Variation	[10]
Triple negative breast cancer	DISAMG6N	Strong	Biomarker	[11]
Breast cancer	DIS7DPX1	moderate	Biomarker	[12]
Breast carcinoma	DIS2UE88	moderate	Biomarker	[12]
Childhood acute lymphoblastic leukemia	DISJ5D6U	Limited	Biomarker	[13]
Pancreatic cancer	DISJC981	Limited	Altered Expression	[3]

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 PR domain zinc finger protein 14 (PRDM14).	[14]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene increases the methylation of PR domain zinc finger protein 14 (PRDM14).	[19]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Tretinoin	DM49DUI	Approved	Tretinoin affects the expression of PR domain zinc finger protein 14 (PRDM14).	[15]
Acetaminophen	DMUIE76	Approved	Acetaminophen increases the expression of PR domain zinc finger protein 14 (PRDM14).	[16]
Fluorouracil	DMUM7HZ	Approved	Fluorouracil affects the expression of PR domain zinc finger protein 14 (PRDM14).	[17]
Panobinostat	DM58WKG	Approved	Panobinostat increases the expression of PR domain zinc finger protein 14 (PRDM14).	[18]
SNDX-275	DMH7W9X	Phase 3	SNDX-275 increases the expression of PR domain zinc finger protein 14 (PRDM14).	[18]
Belinostat	DM6OC53	Phase 2	Belinostat increases the expression of PR domain zinc finger protein 14 (PRDM14).	[18]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A increases the expression of PR domain zinc finger protein 14 (PRDM14).	[20]
Trichostatin A	DM9C8NX	Investigative	Trichostatin A decreases the expression of PR domain zinc finger protein 14 (PRDM14).	[21]

References

• [1] The Pluripotency Regulator PRDM14 Requires Hematopoietic Regulator CBFA2T3 to Initiate Leukemia in Mice.Mol Cancer Res. 2019 Jul;17(7):1468-1479. doi: 10.1158/1541-7786.MCR-18-1327. Epub 2019 Apr 23.
• [2] Methylation-mediated repression of PRDM14 contributes to apoptosis evasion in HPV-positive cancers.Carcinogenesis. 2014 Nov;35(11):2611-8. doi: 10.1093/carcin/bgu197. Epub 2014 Sep 18.
• [3] PRDM14 is overexpressed in chronic pancreatitis prior to pancreatic cancer.FEBS Open Bio. 2018 Sep 17;8(10):1733-1741. doi: 10.1002/2211-5463.12519. eCollection 2018 Oct.
• [4] PRDM14 promotes malignant phenotype and correlates with poor prognosis in colorectal cancer.Clin Transl Oncol. 2020 Jul;22(7):1126-1137. doi: 10.1007/s12094-019-02239-z. Epub 2019 Nov 18.
• [5] PRDM14 is expressed in germ cell tumors with constitutive overexpression altering human germline differentiation and proliferation.Stem Cell Res. 2018 Mar;27:46-56. doi: 10.1016/j.scr.2017.12.016. Epub 2018 Jan 4.
• [6] High expression of PRDM14 correlates with cell differentiation and is a novel prognostic marker in resected non-small cell lung cancer.Med Oncol. 2013;30(3):605. doi: 10.1007/s12032-013-0605-9. Epub 2013 May 21.
• [7] Identification of nine new susceptibility loci for testicular cancer, including variants near DAZL and PRDM14.Nat Genet. 2013 Jun;45(6):686-9. doi: 10.1038/ng.2635. Epub 2013 May 12.
• [8] PRDM14 promotes the migration of human non-small cell lung cancer through extracellular matrix degradation in vitro.Chin Med J (Engl). 2015 Feb 5;128(3):373-7. doi: 10.4103/0366-6999.150109.
• [9] Genome-Wide Association Study Detected Novel Susceptibility Genes for Schizophrenia and Shared Trans-Populations/Diseases Genetic Effect.Schizophr Bull. 2019 Jun 18;45(4):824-834. doi: 10.1093/schbul/sby140.
• [10] Identification of 19 new risk loci and potential regulatory mechanisms influencing susceptibility to testicular germ cell tumor.Nat Genet. 2017 Jul;49(7):1133-1140. doi: 10.1038/ng.3896. Epub 2017 Jun 12.
• [11] PRDM14 directly interacts with heat shock proteins HSP90 and glucose-regulated protein 78.Cancer Sci. 2018 Feb;109(2):373-383. doi: 10.1111/cas.13458. Epub 2017 Dec 28.
• [12] Silencing PRDM14 via Oligonucleotide Therapeutics Suppresses Tumorigenicity and Metastasis of Breast Cancer.Methods Mol Biol. 2019;1974:233-243. doi: 10.1007/978-1-4939-9220-1_18.
• [13] The zinc finger SET domain gene Prdm14 is overexpressed in lymphoblastic lymphomas with retroviral insertions at Evi32.PLoS One. 2008;3(11):e3823. doi: 10.1371/journal.pone.0003823. Epub 2008 Nov 27.
• [14] 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.
• [15] Molecular characterization of a toxicological tipping point during human stem cell differentiation. Reprod Toxicol. 2020 Jan;91:1-13. doi: 10.1016/j.reprotox.2019.10.001. Epub 2019 Oct 7.
• [16] Blood transcript immune signatures distinguish a subset of people with elevated serum ALT from others given acetaminophen. Clin Pharmacol Ther. 2016 Apr;99(4):432-41.
• [17] New insights into the mechanisms underlying 5-fluorouracil-induced intestinal toxicity based on transcriptomic and metabolomic responses in human intestinal organoids. Arch Toxicol. 2021 Aug;95(8):2691-2718. doi: 10.1007/s00204-021-03092-2. Epub 2021 Jun 20.
• [18] A transcriptome-based classifier to identify developmental toxicants by stem cell testing: design, validation and optimization for histone deacetylase inhibitors. Arch Toxicol. 2015 Sep;89(9):1599-618.
• [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 profiling in Ishikawa cells: a fingerprint for estrogen active compounds. Toxicol Appl Pharmacol. 2009 Apr 1;236(1):85-96.
• [21] 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.