Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OT70OQQV)

• DOT Name: Coiled-coil domain-containing protein 134 (CCDC134)
• Gene Name: CCDC134
• Related Disease:
  Arthritis
  Rheumatoid arthritis
  Advanced cancer
  Alzheimer disease
  Autoimmune disease
  Breast carcinoma
  Gastric cancer
  Liver cancer
  Multiple sclerosis
  Nervous system inflammation
  Precancerous condition
  Stomach cancer
  Osteogenesis imperfecta
  Osteogenesis imperfecta, IIA 22
• UniProt ID: CC134_HUMAN
• Pfam ID: PF15002
• Sequence:
  MDLLQFLAFLFVLLLSGMGATGTLRTSLDPSLEIYKKMFEVKRREQLLALKNLAQLNDIH
  QQYKILDVMLKGLFKVLEDSRTVLTAADVLPDGPFPQDEKLKDAFSHVVENTAFFGDVVL
  RFPRIVHYYFDHNSNWNLLIRWGISFCNQTGVFNQGPHSPILSLMAQELGISEKDSNFQN
  PFKIDRTEFIPSTDPFQKALREEEKRRKKEEKRKEIRKGPRISRSQSEL
• Function: In extracellular secreted form, promotes proliferation and activation of CD8(+) T cells, suggesting a cytokine-like function. Enhances cytotoxic anti-tumor activity of CD8(+) T cells. May inhibit ERK and JNK signaling activity. May suppress cell migration and invasion activity, via its effects on ERK and JNK signaling. Has a critical role in the regulation of osteogenesis and bone development ; In the nucleus, enhances stability of the PCAF histone acetyltransferase (HAT) complex member TADA2A and thus promotes PCAF-mediated H3K14 and H4K8 HAT activity. May inhibit TADA2A-mediated TP53/p53 'Lys-321' acetylation, leading to reduced TP53 stability and transcriptional activity. May also promote TADA2A-mediated XRCC6 acetylation thus facilitating cell apoptosis in response to DNA damage.
• Tissue Specificity: Expressed in cervical gland, cervical squamous epithelium, endometrium, stomach, kidney distal convoluted tubule, spermatogenic cells in testis, mammary gland, liver and striated muscle (at protein level) . Also detected in placenta . Highest expression in testis relative to other tissues . Detected in T cells and dendritic cells; highly expressed in activated CD8(+) T cells, and also expressed at lower levels in CD4(+) T cells .

Molecular Interaction Atlas (MIA) of This DOT

14 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Arthritis	DIST1YEL	Definitive	Biomarker	[1]
Rheumatoid arthritis	DISTSB4J	Definitive	Biomarker	[1]
Advanced cancer	DISAT1Z9	Strong	Biomarker	[2]
Alzheimer disease	DISF8S70	Strong	Genetic Variation	[3]
Autoimmune disease	DISORMTM	Strong	Biomarker	[4]
Breast carcinoma	DIS2UE88	Strong	Genetic Variation	[5]
Gastric cancer	DISXGOUK	Strong	Altered Expression	[2]
Liver cancer	DISDE4BI	Strong	Biomarker	[6]
Multiple sclerosis	DISB2WZI	Strong	Altered Expression	[4]
Nervous system inflammation	DISB3X5A	Strong	Altered Expression	[4]
Precancerous condition	DISV06FL	Strong	Biomarker	[6]
Stomach cancer	DISKIJSX	Strong	Altered Expression	[2]
Osteogenesis imperfecta	DIS7XQSD	Limited	Autosomal recessive	[7]
Osteogenesis imperfecta, IIA 22	DISS24AB	Limited	Unknown	[8]

1 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 Coiled-coil domain-containing protein 134 (CCDC134).	[9]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Tretinoin	DM49DUI	Approved	Tretinoin decreases the expression of Coiled-coil domain-containing protein 134 (CCDC134).	[10]
Cisplatin	DMRHGI9	Approved	Cisplatin increases the expression of Coiled-coil domain-containing protein 134 (CCDC134).	[11]
Urethane	DM7NSI0	Phase 4	Urethane increases the expression of Coiled-coil domain-containing protein 134 (CCDC134).	[12]
Amiodarone	DMUTEX3	Phase 2/3 Trial	Amiodarone increases the expression of Coiled-coil domain-containing protein 134 (CCDC134).	[13]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene increases the expression of Coiled-coil domain-containing protein 134 (CCDC134).	[14]
PMID28460551-Compound-2	DM4DOUB	Patented	PMID28460551-Compound-2 decreases the expression of Coiled-coil domain-containing protein 134 (CCDC134).	[15]

References

• [1] Amelioration of adjuvant-induced arthritis in CCDC134-overexpressing transgenic mice.Biochem Biophys Res Commun. 2017 Aug 19;490(2):111-116. doi: 10.1016/j.bbrc.2017.05.166. Epub 2017 May 29.
• [2] CCDC134 is down-regulated in gastric cancer and its silencing promotes cell migration and invasion of GES-1 and AGS cells via the MAPK pathway.Mol Cell Biochem. 2013 Jan;372(1-2):1-8. doi: 10.1007/s11010-012-1418-4. Epub 2012 Aug 18.
• [3] Genome-wide association study of CSF biomarkers Abeta1-42, t-tau, and p-tau181p in the ADNI cohort.Neurology. 2011 Jan 4;76(1):69-79. doi: 10.1212/WNL.0b013e318204a397. Epub 2010 Dec 1.
• [4] CCDC134 ameliorated experimental autoimmune encephalomyelitis by suppressing Th1 and Th17 cells.Brain Behav Immun. 2018 Jul;71:158-168. doi: 10.1016/j.bbi.2018.03.015. Epub 2018 Mar 14.
• [5] Association analysis identifies 65 new breast cancer risk loci.Nature. 2017 Nov 2;551(7678):92-94. doi: 10.1038/nature24284. Epub 2017 Oct 23.
• [6] Multiple genes exhibit phenobarbital-induced constitutive active/androstane receptor-mediated DNA methylation changes during liver tumorigenesis and in liver tumors.Toxicol Sci. 2009 Apr;108(2):273-89. doi: 10.1093/toxsci/kfp031. Epub 2009 Feb 20.
• [7] Classification of Genes: Standardized Clinical Validity Assessment of Gene-Disease Associations Aids Diagnostic Exome Analysis and Reclassifications. Hum Mutat. 2017 May;38(5):600-608. doi: 10.1002/humu.23183. Epub 2017 Feb 13.
• [8] Homozygous Loss-of-Function Mutations in CCDC134 Are Responsible for a Severe Form of Osteogenesis Imperfecta. J Bone Miner Res. 2020 Aug;35(8):1470-1480. doi: 10.1002/jbmr.4011. Epub 2020 Apr 14.
• [9] 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.
• [10] Transcriptional and Metabolic Dissection of ATRA-Induced Granulocytic Differentiation in NB4 Acute Promyelocytic Leukemia Cells. Cells. 2020 Nov 5;9(11):2423. doi: 10.3390/cells9112423.
• [11] Activation of AIFM2 enhances apoptosis of human lung cancer cells undergoing toxicological stress. Toxicol Lett. 2016 Sep 6;258:227-236.
• [12] Ethyl carbamate induces cell death through its effects on multiple metabolic pathways. Chem Biol Interact. 2017 Nov 1;277:21-32.
• [13] Identification by automated screening of a small molecule that selectively eliminates neural stem cells derived from hESCs but not dopamine neurons. PLoS One. 2009 Sep 23;4(9):e7155.
• [14] Identification of a transcriptomic signature of food-relevant genotoxins in human HepaRG hepatocarcinoma cells. Food Chem Toxicol. 2020 Jun;140:111297. doi: 10.1016/j.fct.2020.111297. Epub 2020 Mar 28.
• [15] 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.