Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTLCXC6H)

• DOT Name: Cytoplasmic polyadenylation element-binding protein 1 (CPEB1)
• Synonyms: CPE-BP1; CPE-binding protein 1; h-CPEB; hCPEB-1
• Gene Name: CPEB1
• Related Disease:
  Adult glioblastoma
  Advanced cancer
  Astrocytoma
  Breast cancer
  Breast carcinoma
  Endometrial cancer
  Endometrial carcinoma
  Gastric cancer
  Glioblastoma multiforme
  Lung adenocarcinoma
  Male infertility
  Malignant glioma
  Neoplasm
  Non-small-cell lung cancer
  Schizophrenia
  Small lymphocytic lymphoma
  Stomach cancer
  Female hypogonadism
  Glioma
  Primary biliary cholangitis
  Anxiety
  Anxiety disorder
  Fragile X syndrome
  Hepatocellular carcinoma
  Nervous system disease
• UniProt ID: CPEB1_HUMAN
• PDB ID: 2M13; 2MKE; 2MKH; 2MKK; 2N1O
• Pfam ID: PF16368 ; PF16366 ; PF16367
• Sequence:
  MALSLEEEAGRIKDCWDNQEAPALSTCSNANIFRRINAILDNSLDFSRVCTTPINRGIHD
  HLPDFQDSEETVTSRMLFPTSAQESSRGLPDANDLCLGLQSLSLTGWDRPWSTQDSDSSA
  QSSTHSVLSMLHNPLGNVLGKPPLSFLPLDPLGSDLVDKFPAPSVRGSRLDTRPILDSRS
  SSPSDSDTSGFSSGSDHLSDLISSLRISPPLPFLSLSGGGPRDPLKMGVGSRMDQEQAAL
  AAVTPSPTSASKRWPGASVWPSWDLLEAPKDPFSIEREARLHRQAAAVNEATCTWSGQLP
  PRNYKNPIYSCKVFLGGVPWDITEAGLVNTFRVFGSLSVEWPGKDGKHPRCPPKGNMPKG
  YVYLVFELEKSVRSLLQACSHDPLSPDGLSEYYFKMSSRRMRCKEVQVIPWVLADSNFVR
  SPSQRLDPSRTVFVGALHGMLNAEALAAILNDLFGGVVYAGIDTDKHKYPIGSGRVTFNN
  QRSYLKAVSAAFVEIKTTKFTKKVQIDPYLEDSLCHICSSQPGPFFCRDQVCFKYFCRSC
  WHWRHSMEGLRHHSPLMRNQKNRDSS
• Function: Sequence-specific RNA-binding protein that regulates mRNA cytoplasmic polyadenylation and translation initiation during oocyte maturation, early development and at postsynapse sites of neurons. Binds to the cytoplasmic polyadenylation element (CPE), an uridine-rich sequence element (consensus sequence 5'-UUUUUAU-3') within the mRNA 3'-UTR. RNA binding results in a clear conformational change analogous to the Venus fly trap mechanism. In absence of phosphorylation and in association with TACC3 is also involved as a repressor of translation of CPE-containing mRNA; a repression that is relieved by phosphorylation or degradation. Involved in the transport of CPE-containing mRNA to dendrites; those mRNAs may be transported to dendrites in a translationally dormant form and translationally activated at synapses. Its interaction with APLP1 promotes local CPE-containing mRNA polyadenylation and translation activation. Induces the assembly of stress granules in the absence of stress. Required for cell cycle progression, specifically for prophase entry.
• Tissue Specificity: Isoform 1 is expressed in immature oocytes, ovary, brain and heart. Isoform 2 is expressed in brain and heart. Isoform 3 and isoform 4 are expressed in brain. Expressed in breast tumors and several tumor cell lines.
• KEGG Pathway:
  Oocyte meiosis (hsa04114)
  Progesterone-mediated oocyte maturation (hsa04914)

Molecular Interaction Atlas (MIA) of This DOT

25 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Adult glioblastoma	DISVP4LU	Strong	Biomarker	[1]
Advanced cancer	DISAT1Z9	Strong	Biomarker	[2]
Astrocytoma	DISL3V18	Strong	Biomarker	[3]
Breast cancer	DIS7DPX1	Strong	Biomarker	[4]
Breast carcinoma	DIS2UE88	Strong	Biomarker	[4]
Endometrial cancer	DISW0LMR	Strong	Altered Expression	[5]
Endometrial carcinoma	DISXR5CY	Strong	Altered Expression	[5]
Gastric cancer	DISXGOUK	Strong	Biomarker	[6]
Glioblastoma multiforme	DISK8246	Strong	Biomarker	[1]
Lung adenocarcinoma	DISD51WR	Strong	Biomarker	[7]
Male infertility	DISY3YZZ	Strong	Genetic Variation	[8]
Malignant glioma	DISFXKOV	Strong	Genetic Variation	[9]
Neoplasm	DISZKGEW	Strong	Biomarker	[9]
Non-small-cell lung cancer	DIS5Y6R9	Strong	Altered Expression	[10]
Schizophrenia	DISSRV2N	Strong	Genetic Variation	[11]
Small lymphocytic lymphoma	DIS30POX	Strong	Biomarker	[12]
Stomach cancer	DISKIJSX	Strong	Biomarker	[6]
Female hypogonadism	DISWASB4	moderate	Biomarker	[13]
Glioma	DIS5RPEH	moderate	Altered Expression	[9]
Primary biliary cholangitis	DIS43E0O	Disputed	Biomarker	[14]
Anxiety	DISIJDBA	Limited	Biomarker	[15]
Anxiety disorder	DISBI2BT	Limited	Biomarker	[15]
Fragile X syndrome	DISE8W3A	Limited	Biomarker	[15]
Hepatocellular carcinoma	DIS0J828	Limited	Biomarker	[2]
Nervous system disease	DISJ7GGT	Limited	Genetic Variation	[16]

3 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 Cytoplasmic polyadenylation element-binding protein 1 (CPEB1).	[17]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene increases the methylation of Cytoplasmic polyadenylation element-binding protein 1 (CPEB1).	[24]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A decreases the methylation of Cytoplasmic polyadenylation element-binding protein 1 (CPEB1).	[26]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Cupric Sulfate	DMP0NFQ	Approved	Cupric Sulfate increases the expression of Cytoplasmic polyadenylation element-binding protein 1 (CPEB1).	[18]
Cisplatin	DMRHGI9	Approved	Cisplatin decreases the expression of Cytoplasmic polyadenylation element-binding protein 1 (CPEB1).	[19]
Temozolomide	DMKECZD	Approved	Temozolomide decreases the expression of Cytoplasmic polyadenylation element-binding protein 1 (CPEB1).	[20]
Arsenic trioxide	DM61TA4	Approved	Arsenic trioxide increases the expression of Cytoplasmic polyadenylation element-binding protein 1 (CPEB1).	[21]
Decitabine	DMQL8XJ	Approved	Decitabine affects the expression of Cytoplasmic polyadenylation element-binding protein 1 (CPEB1).	[22]
SNDX-275	DMH7W9X	Phase 3	SNDX-275 increases the expression of Cytoplasmic polyadenylation element-binding protein 1 (CPEB1).	[23]
PMID28460551-Compound-2	DM4DOUB	Patented	PMID28460551-Compound-2 increases the expression of Cytoplasmic polyadenylation element-binding protein 1 (CPEB1).	[25]
Trichostatin A	DM9C8NX	Investigative	Trichostatin A increases the expression of Cytoplasmic polyadenylation element-binding protein 1 (CPEB1).	[27]

References

• [1] miR?54?p suppresses cell migration and invasion by targeting CPEB1 in human glioblastoma.Mol Med Rep. 2018 Oct;18(4):3965-3972. doi: 10.3892/mmr.2018.9386. Epub 2018 Aug 14.
• [2] CPEB1 mediates hepatocellular carcinoma cancer stemness and chemoresistance.Cell Death Dis. 2018 Sep 20;9(10):957. doi: 10.1038/s41419-018-0974-2.
• [3] CASC2c as an unfavorable prognosis factor interacts with miR-101 to mediate astrocytoma tumorigenesis.Cell Death Dis. 2017 Mar 2;8(3):e2639. doi: 10.1038/cddis.2017.11.
• [4] CPEB1 mediates epithelial-to-mesenchyme transition and breast cancer metastasis.Oncogene. 2016 Jun 2;35(22):2893-901. doi: 10.1038/onc.2015.350. Epub 2015 Sep 28.
• [5] MicroRNA-183 induces epithelial-mesenchymal transition and promotes endometrial cancer cell migration and invasion in by targeting CPEB1.J Cell Biochem. 2018 Nov;119(10):8123-8137. doi: 10.1002/jcb.26763. Epub 2018 Jun 20.
• [6] CPEB1, a novel gene silenced in gastric cancer: a Drosophila approach.Gut. 2012 Aug;61(8):1115-23. doi: 10.1136/gutjnl-2011-300427. Epub 2011 Nov 3.
• [7] Genome-wide unmasking of epigenetically silenced genes in lung adenocarcinoma from smokers and never smokers.Carcinogenesis. 2014 Jun;35(6):1248-57. doi: 10.1093/carcin/bgt494. Epub 2014 Jan 7.
• [8] A single nucleotide polymorphism in a miR-1302 binding site in CGA increases the risk of idiopathic male infertility.Fertil Steril. 2011 Jul;96(1):34-39.e7. doi: 10.1016/j.fertnstert.2011.04.053. Epub 2011 May 20.
• [9] Somatic CPEB4 and CPEB1 genes mutations spectrum on the prognostic predictive accuracy in patients with high-grade glioma and their clinical significance.J Neurol Sci. 2016 Apr 15;363:80-3. doi: 10.1016/j.jns.2016.02.032. Epub 2016 Feb 16.
• [10] Alternative polyadenylation is associated with lower expression of PABPN1 and poor prognosis in non-small cell lung cancer.Cancer Sci. 2014 Sep;105(9):1135-41. doi: 10.1111/cas.12472. Epub 2014 Sep 3.
• [11] 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.
• [12] Common variants at 2q37.3, 8q24.21, 15q21.3 and 16q24.1 influence chronic lymphocytic leukemia risk.Nat Genet. 2010 Feb;42(2):132-6. doi: 10.1038/ng.510. Epub 2010 Jan 10.
• [13] Deletion of CPEB1 Gene: A Rare but Recurrent Cause of Premature Ovarian Insufficiency.J Clin Endocrinol Metab. 2016 May;101(5):2099-104. doi: 10.1210/jc.2016-1291. Epub 2016 Mar 22.
• [14] Sequential Functions of CPEB1 and CPEB4 Regulate Pathologic Expression of Vascular Endothelial Growth Factor and Angiogenesis in Chronic Liver Disease.Gastroenterology. 2016 Apr;150(4):982-97.e30. doi: 10.1053/j.gastro.2015.11.038. Epub 2015 Nov 26.
• [15] Anxiolytic effect of CPEB1 knockdown on the amygdala of a mouse model of inflammatory pain.Brain Res Bull. 2018 Mar;137:156-165. doi: 10.1016/j.brainresbull.2017.12.002. Epub 2017 Dec 11.
• [16] Cytoplasmic polyadenylation element binding proteins in development, health, and disease.Annu Rev Cell Dev Biol. 2014;30:393-415. doi: 10.1146/annurev-cellbio-101011-155831. Epub 2014 Jul 14.
• [17] 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.
• [18] Physiological and toxicological transcriptome changes in HepG2 cells exposed to copper. Physiol Genomics. 2009 Aug 7;38(3):386-401.
• [19] Activation of AIFM2 enhances apoptosis of human lung cancer cells undergoing toxicological stress. Toxicol Lett. 2016 Sep 6;258:227-236.
• [20] 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.
• [21] Essential role of cell cycle regulatory genes p21 and p27 expression in inhibition of breast cancer cells by arsenic trioxide. Med Oncol. 2011 Dec;28(4):1225-54.
• [22] Epigenetic silencing of novel tumor suppressors in malignant melanoma. Cancer Res. 2006 Dec 1;66(23):11187-93. doi: 10.1158/0008-5472.CAN-06-1274.
• [23] 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.
• [24] 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.
• [25] Cell-based two-dimensional morphological assessment system to predict cancer drug-induced cardiotoxicity using human induced pluripotent stem cell-derived cardiomyocytes. Toxicol Appl Pharmacol. 2019 Nov 15;383:114761. doi: 10.1016/j.taap.2019.114761. Epub 2019 Sep 15.
• [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.