Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTO295IH)

• DOT Name: Coiled-coil domain-containing protein 8 (CCDC8)
• Gene Name: CCDC8
• Related Disease:
  3M syndrome 1
  3M syndrome 3
  Advanced cancer
  Benign prostatic hyperplasia
  Breast cancer
  Breast carcinoma
  Central nervous system lymphoma
  Clear cell renal carcinoma
  Fetal growth restriction
  Glioblastoma multiforme
  Head-neck squamous cell carcinoma
  Hepatocellular carcinoma
  Hyperinsulinemia
  Lung adenocarcinoma
  Lung cancer
  Lung carcinoma
  Neoplasm
  Non-small-cell lung cancer
  Renal cell carcinoma
  rubella
  Spinal muscular atrophy
  Type-1/2 diabetes
  Metastatic malignant neoplasm
  Tuberous sclerosis
  3-M syndrome
  Arteriosclerosis
  Atherosclerosis
  Gastric cancer
  Melanoma
  Prostate cancer
  Prostate carcinoma
  Spinocerebellar ataxia type 40
  Stomach cancer
• UniProt ID: CCDC8_HUMAN
• PDB ID: 4LG6
• Sequence:
  MLQIGEDVDYLLIPREVRLAGGVWRVISKPATKEAEFRERLTQFLEEEGRTLEDVARIME
  KSTPHPPQPPKKPKEPRVRRRVQQMVTPPPRLVVGTYDSSNASDSEFSDFETSRDKSRQG
  PRRGKKVRKMPVSYLGSKFLGSDLESEDDEELVEAFLRRQEKQPSAPPARRRVNLPVPMF
  EDNLGPQLSKADRWREYVSQVSWGKLKRRVKGWAPRAGPGVGEARLASTAVESAGVSSAP
  EGTSPGDRLGNAGDVCVPQASPRRWRPKINWASFRRRRKEQTAPTGQGADIEADQGGEAA
  DSQREEAIADQREGAAGNQRAGAPADQGAEAADNQREEAADNQRAGAPAEEGAEAADNQR
  EEAADNQRAEAPADQRSQGTDNHREEAADNQRAEAPADQGSEVTDNQREEAVHDQRERAP
  AVQGADNQRAQARAGQRAEAAHNQRAGAPGIQEAEVSAAQGTTGTAPGARARKQVKTVRF
  QTPGRFSWFCKRRRAFWHTPRLPTLPKRVPRAGEARNLRVLRAEARAEAEQGEQEDQL
• Function: Core component of the 3M complex, a complex required to regulate microtubule dynamics and genome integrity. It is unclear how the 3M complex regulates microtubules, it could act by controlling the level of a microtubule stabilizer. Required for localization of CUL7 to the centrosome.
• Tissue Specificity: Widely expressed with low levels in spleen, skeletal muscle, small intestine, kidney and liver.
• Reactome Pathway: Neddylation (R-HSA-8951664)

Molecular Interaction Atlas (MIA) of This DOT

33 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
3M syndrome 1	DISHSKS7	Strong	GermlineCausalMutation	[1]
3M syndrome 3	DISXWV3X	Strong	Autosomal recessive	[1]
Advanced cancer	DISAT1Z9	Strong	Biomarker	[2]
Benign prostatic hyperplasia	DISI3CW2	Strong	Biomarker	[3]
Breast cancer	DIS7DPX1	Strong	Altered Expression	[4]
Breast carcinoma	DIS2UE88	Strong	Altered Expression	[4]
Central nervous system lymphoma	DISBYQTA	Strong	Biomarker	[5]
Clear cell renal carcinoma	DISBXRFJ	Strong	Genetic Variation	[6]
Fetal growth restriction	DIS5WEJ5	Strong	Biomarker	[7]
Glioblastoma multiforme	DISK8246	Strong	Biomarker	[5]
Head-neck squamous cell carcinoma	DISF7P24	Strong	Biomarker	[8]
Hepatocellular carcinoma	DIS0J828	Strong	Genetic Variation	[9]
Hyperinsulinemia	DISIDWT6	Strong	Biomarker	[10]
Lung adenocarcinoma	DISD51WR	Strong	Biomarker	[11]
Lung cancer	DISCM4YA	Strong	Biomarker	[2]
Lung carcinoma	DISTR26C	Strong	Biomarker	[2]
Neoplasm	DISZKGEW	Strong	Altered Expression	[2]
Non-small-cell lung cancer	DIS5Y6R9	Strong	Biomarker	[2]
Renal cell carcinoma	DISQZ2X8	Strong	Genetic Variation	[6]
rubella	DISXUI9P	Strong	Biomarker	[12]
Spinal muscular atrophy	DISTLKOB	Strong	Biomarker	[13]
Type-1/2 diabetes	DISIUHAP	Strong	Biomarker	[14]
Metastatic malignant neoplasm	DIS86UK6	moderate	Biomarker	[15]
Tuberous sclerosis	DISEMUGZ	moderate	Biomarker	[16]
3-M syndrome	DISGKJY3	Supportive	Autosomal recessive	[17]
Arteriosclerosis	DISK5QGC	Limited	Biomarker	[18]
Atherosclerosis	DISMN9J3	Limited	Biomarker	[18]
Gastric cancer	DISXGOUK	Limited	Biomarker	[19]
Melanoma	DIS1RRCY	Limited	Biomarker	[20]
Prostate cancer	DISF190Y	Limited	Biomarker	[2]
Prostate carcinoma	DISMJPLE	Limited	Biomarker	[21]
Spinocerebellar ataxia type 40	DISYX3KE	Limited	Autosomal dominant	[22]
Stomach cancer	DISKIJSX	Limited	Biomarker	[19]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Valproate	DMCFE9I	Approved	Valproate increases the expression of Coiled-coil domain-containing protein 8 (CCDC8).	[23]
Doxorubicin	DMVP5YE	Approved	Doxorubicin decreases the expression of Coiled-coil domain-containing protein 8 (CCDC8).	[24]
Marinol	DM70IK5	Approved	Marinol decreases the expression of Coiled-coil domain-containing protein 8 (CCDC8).	[25]
Cannabidiol	DM0659E	Approved	Cannabidiol decreases the expression of Coiled-coil domain-containing protein 8 (CCDC8).	[26]
Hydroquinone	DM6AVR4	Approved	Hydroquinone decreases the expression of Coiled-coil domain-containing protein 8 (CCDC8).	[27]
Sodium lauryl sulfate	DMLJ634	Approved	Sodium lauryl sulfate decreases the expression of Coiled-coil domain-containing protein 8 (CCDC8).	[28]
Formaldehyde	DM7Q6M0	Investigative	Formaldehyde decreases the expression of Coiled-coil domain-containing protein 8 (CCDC8).	[29]

References

• [1] Exome sequencing identifies CCDC8 mutations in 3-M syndrome, suggesting that CCDC8 contributes in a pathway with CUL7 and OBSL1 to control human growth. Am J Hum Genet. 2011 Jul 15;89(1):148-53. doi: 10.1016/j.ajhg.2011.05.028. Epub 2011 Jul 7.
• [2] Coiled-coil domain-containing protein 8 inhibits the invasiveness and migration of non-small cell lung cancer cells.Hum Pathol. 2016 Oct;56:64-73. doi: 10.1016/j.humpath.2016.06.001. Epub 2016 Jun 21.
• [3] Preferential humoral immune response in prostate cancer to cellular proteins p90 and p62 in a panel of tumor-associated antigens.Prostate. 2005 May 15;63(3):252-8. doi: 10.1002/pros.20181.
• [4] RSK-mediated down-regulation of PDCD4 is required for proliferation, survival, and migration in a model of triple-negative breast cancer.Oncotarget. 2016 May 10;7(19):27567-83. doi: 10.18632/oncotarget.8375.
• [5] Primary central nervous system lymphoma and atypical glioblastoma: differentiation using the initial area under the curve derived from dynamic contrast-enhanced MR and the apparent diffusion coefficient.Eur Radiol. 2017 Apr;27(4):1344-1351. doi: 10.1007/s00330-016-4484-2. Epub 2016 Jul 19.
• [6] Genome-wide methylation analysis identifies epigenetically inactivated candidate tumour suppressor genes in renal cell carcinoma.Oncogene. 2011 Mar 24;30(12):1390-401. doi: 10.1038/onc.2010.525. Epub 2010 Dec 6.
• [7] Impaired plasma membrane localization of ubiquitin ligase complex underlies 3-M syndrome development.J Clin Invest. 2019 Jul 25;129(10):4393-4407. doi: 10.1172/JCI129107.
• [8] p90 ribosomal S6 kinase 2 promotes invasion and metastasis of human head and neck squamous cell carcinoma cells.J Clin Invest. 2010 Apr;120(4):1165-77. doi: 10.1172/JCI40582. Epub 2010 Mar 15.
• [9] Genome-Wide Association Study of MKI67 Expression and its Clinical Implications in HBV-Related Hepatocellular Carcinoma in Southern China.Cell Physiol Biochem. 2017;42(4):1342-1357. doi: 10.1159/000478963. Epub 2017 Jul 13.
• [10] Effect of sildenafil citrate treatment in the eNOS knockout mouse model of fetal growth restriction on long-term cardiometabolic outcomes in male offspring.Pharmacol Res. 2018 Nov;137:122-134. doi: 10.1016/j.phrs.2018.09.023. Epub 2018 Oct 5.
• [11] Inhibition of p90 ribosomal S6 kinase attenuates cell migration and proliferation of the human lung adenocarcinoma through phospho-GSK-3 and osteopontin.Mol Cell Biochem. 2016 Jul;418(1-2):21-9. doi: 10.1007/s11010-016-2727-9. Epub 2016 May 28.
• [12] Analysis of the function of cytoplasmic fibers formed by the rubella virus nonstructural replicase proteins.Virology. 2010 Oct 25;406(2):212-27. doi: 10.1016/j.virol.2010.07.025. Epub 2010 Aug 8.
• [13] Normalization of Patient-Identified Plasma Biomarkers in SMN7 Mice following Postnatal SMN Restoration.PLoS One. 2016 Dec 1;11(12):e0167077. doi: 10.1371/journal.pone.0167077. eCollection 2016.
• [14] The Influencing Factors of Serum Lipids among Middle-aged Women in Northeast China.Iran J Public Health. 2018 Nov;47(11):1660-1666.
• [15] RSK2 signals through stathmin to promote microtubule dynamics and tumor metastasis.Oncogene. 2016 Oct 13;35(41):5412-5421. doi: 10.1038/onc.2016.79. Epub 2016 Apr 4.
• [16] Tumor-promoting phorbol esters and activated Ras inactivate the tuberous sclerosis tumor suppressor complex via p90 ribosomal S6 kinase.Proc Natl Acad Sci U S A. 2004 Sep 14;101(37):13489-94. doi: 10.1073/pnas.0405659101. Epub 2004 Sep 1.
• [17] Three M Syndrome. 2002 Mar 25 [updated 2019 Feb 7]. In: Adam MP, Feldman J, Mirzaa GM, Pagon RA, Wallace SE, Bean LJH, Gripp KW, Amemiya A, editors. GeneReviews(?) [Internet]. Seattle (WA): University of Washington, Seattle; 1993C2024.
• [18] A crucial role for p90RSK-mediated reduction of ERK5 transcriptional activity in endothelial dysfunction and atherosclerosis.Circulation. 2013 Jan 29;127(4):486-99. doi: 10.1161/CIRCULATIONAHA.112.116988. Epub 2012 Dec 14.
• [19] JMJD2A sensitizes gastric cancer to chemotherapy by cooperating with CCDC8.Gastric Cancer. 2020 May;23(3):426-436. doi: 10.1007/s10120-019-01024-9. Epub 2019 Nov 1.
• [20] Fisetin targets YB-1/RSK axis independent of its effect on ERK signaling: insights from in vitro and in vivo melanoma models.Sci Rep. 2018 Oct 24;8(1):15726. doi: 10.1038/s41598-018-33879-w.
• [21] The serine/threonine protein kinase, p90 ribosomal S6 kinase, is an important regulator of prostate cancer cell proliferation.Cancer Res. 2005 Apr 15;65(8):3108-16. doi: 10.1158/0008-5472.CAN-04-3151.
• [22] A novel missense mutation in CCDC88C activates the JNK pathway and causes a dominant form of spinocerebellar ataxia. J Med Genet. 2014 Sep;51(9):590-5. doi: 10.1136/jmedgenet-2014-102333. Epub 2014 Jul 25.
• [23] Human embryonic stem cell-derived test systems for developmental neurotoxicity: a transcriptomics approach. Arch Toxicol. 2013 Jan;87(1):123-43.
• [24] Bringing in vitro analysis closer to in vivo: studying doxorubicin toxicity and associated mechanisms in 3D human microtissues with PBPK-based dose modelling. Toxicol Lett. 2018 Sep 15;294:184-192.
• [25] THC exposure of human iPSC neurons impacts genes associated with neuropsychiatric disorders. Transl Psychiatry. 2018 Apr 25;8(1):89. doi: 10.1038/s41398-018-0137-3.
• [26] Cannabidiol enhances cytotoxicity of anti-cancer drugs in human head and neck squamous cell carcinoma. Sci Rep. 2020 Nov 26;10(1):20622. doi: 10.1038/s41598-020-77674-y.
• [27] Keratinocyte-derived IL-36gama plays a role in hydroquinone-induced chemical leukoderma through inhibition of melanogenesis in human epidermal melanocytes. Arch Toxicol. 2019 Aug;93(8):2307-2320.
• [28] CXCL14 downregulation in human keratinocytes is a potential biomarker for a novel in vitro skin sensitization test. Toxicol Appl Pharmacol. 2020 Jan 1;386:114828. doi: 10.1016/j.taap.2019.114828. Epub 2019 Nov 14.
• [29] Gene expression changes in primary human nasal epithelial cells exposed to formaldehyde in vitro. Toxicol Lett. 2010 Oct 5;198(2):289-95.