Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTF5JHQ0)

• DOT Name: Semaphorin-4C (SEMA4C)
• Gene Name: SEMA4C
• Related Disease:
  Breast carcinoma
  Advanced cancer
  Bone osteosarcoma
  Breast cancer
  Non-small-cell lung cancer
  Osteosarcoma
  Hepatocellular carcinoma
• UniProt ID: SEM4C_HUMAN
• PDB ID: 6N5Z
• Pfam ID: PF01437 ; PF01403
• Sequence:
  MAPHWAVWLLAARLWGLGIGAEVWWNLVPRKTVSSGELATVVRRFSQTGIQDFLTLTLTE
  PTGLLYVGAREALFAFSMEALELQGAISWEAPVEKKTECIQKGKNNQTECFNFIRFLQPY
  NASHLYVCGTYAFQPKCTYVNMLTFTLEHGEFEDGKGKCPYDPAKGHAGLLVDGELYSAT
  LNNFLGTEPIILRNMGPHHSMKTEYLAFWLNEPHFVGSAYVPESVGSFTGDDDKVYFFFR
  ERAVESDCYAEQVVARVARVCKGDMGGARTLQRKWTTFLKARLACSAPNWQLYFNQLQAM
  HTLQDTSWHNTTFFGVFQAQWGDMYLSAICEYQLEEIQRVFEGPYKEYHEEAQKWDRYTD
  PVPSPRPGSCINNWHRRHGYTSSLELPDNILNFVKKHPLMEEQVGPRWSRPLLVKKGTNF
  THLVADRVTGLDGATYTVLFIGTGDGWLLKAVSLGPWVHLIEELQLFDQEPMRSLVLSQS
  KKLLFAGSRSQLVQLPVADCMKYRSCADCVLARDPYCAWSVNTSRCVAVGGHSGSLLIQH
  VMTSDTSGICNLRGSKKVRPTPKNITVVAGTDLVLPCHLSSNLAHARWTFGGRDLPAEQP
  GSFLYDARLQALVVMAAQPRHAGAYHCFSEEQGARLAAEGYLVAVVAGPSVTLEARAPLE
  NLGLVWLAVVALGAVCLVLLLLVLSLRRRLREELEKGAKATERTLVYPLELPKEPTSPPF
  RPCPEPDEKLWDPVGYYYSDGSLKIVPGHARCQPGGGPPSPPPGIPGQPLPSPTRLHLGG
  GRNSNANGYVRLQLGGEDRGGLGHPLPELADELRRKLQQRQPLPDSNPEESSV
• Function: Cell surface receptor for PLXNB2 that plays an important role in cell-cell signaling. PLXNB2 binding promotes downstream activation of RHOA and phosphorylation of ERBB2 at 'Tyr-1248'. Required for normal brain development, axon guidance and cell migration. Probable signaling receptor which may play a role in myogenic differentiation through activation of the stress-activated MAPK cascade.
• KEGG Pathway: Axon guidance (hsa04360)

Molecular Interaction Atlas (MIA) of This DOT

7 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Breast carcinoma	DIS2UE88	Definitive	Altered Expression	[1]
Advanced cancer	DISAT1Z9	Strong	Altered Expression	[2]
Bone osteosarcoma	DIST1004	Strong	Biomarker	[2]
Breast cancer	DIS7DPX1	Strong	Altered Expression	[3]
Non-small-cell lung cancer	DIS5Y6R9	Strong	Biomarker	[4]
Osteosarcoma	DISLQ7E2	Strong	Biomarker	[2]
Hepatocellular carcinoma	DIS0J828	Limited	Biomarker	[5]

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 Semaphorin-4C (SEMA4C).	[6]
Arsenic	DMTL2Y1	Approved	Arsenic affects the methylation of Semaphorin-4C (SEMA4C).	[11]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene increases the methylation of Semaphorin-4C (SEMA4C).	[15]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Ciclosporin	DMAZJFX	Approved	Ciclosporin increases the expression of Semaphorin-4C (SEMA4C).	[7]
Acetaminophen	DMUIE76	Approved	Acetaminophen decreases the expression of Semaphorin-4C (SEMA4C).	[8]
Doxorubicin	DMVP5YE	Approved	Doxorubicin decreases the expression of Semaphorin-4C (SEMA4C).	[9]
Cisplatin	DMRHGI9	Approved	Cisplatin increases the expression of Semaphorin-4C (SEMA4C).	[10]
Vorinostat	DMWMPD4	Approved	Vorinostat decreases the expression of Semaphorin-4C (SEMA4C).	[12]
Triclosan	DMZUR4N	Approved	Triclosan increases the expression of Semaphorin-4C (SEMA4C).	[13]
DNCB	DMDTVYC	Phase 2	DNCB increases the expression of Semaphorin-4C (SEMA4C).	[14]
SB-431542	DM0YOXQ	Preclinical	SB-431542 increases the expression of Semaphorin-4C (SEMA4C).	[16]

References

• [1] Semaphorin 4C Promotes Macrophage Recruitment and Angiogenesis in Breast Cancer.Mol Cancer Res. 2019 Oct;17(10):2015-2028. doi: 10.1158/1541-7786.MCR-18-0933. Epub 2019 Jul 15.
• [2] SEMA4C is a novel target to limit osteosarcoma growth, progression, and metastasis.Oncogene. 2020 Jan;39(5):1049-1062. doi: 10.1038/s41388-019-1041-x. Epub 2019 Oct 3.
• [3] Reverse signaling by semaphorin 4C elicits SMAD1/5- and ID1/3-dependent invasive reprogramming in cancer cells.Sci Signal. 2019 Aug 20;12(595):eaav2041. doi: 10.1126/scisignal.aav2041.
• [4] MiR-138 inhibits cell proliferation and reverses epithelial-mesenchymal transition in non-small cell lung cancer cells by targeting GIT1 and SEMA4C.J Cell Mol Med. 2015 Dec;19(12):2793-805. doi: 10.1111/jcmm.12666. Epub 2015 Aug 18.
• [5] MiR-205 suppresses tumor growth, invasion, and epithelial-mesenchymal transition by targeting SEMA4C in hepatocellular carcinoma.FASEB J. 2018 May 25:fj201800113R. doi: 10.1096/fj.201800113R. Online ahead of print.
• [6] 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.
• [7] Integrating multiple omics to unravel mechanisms of Cyclosporin A induced hepatotoxicity in vitro. Toxicol In Vitro. 2015 Apr;29(3):489-501.
• [8] Multiple microRNAs function as self-protective modules in acetaminophen-induced hepatotoxicity in humans. Arch Toxicol. 2018 Feb;92(2):845-858.
• [9] 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.
• [10] Low doses of cisplatin induce gene alterations, cell cycle arrest, and apoptosis in human promyelocytic leukemia cells. Biomark Insights. 2016 Aug 24;11:113-21.
• [11] Prenatal arsenic exposure and the epigenome: identifying sites of 5-methylcytosine alterations that predict functional changes in gene expression in newborn cord blood and subsequent birth outcomes. Toxicol Sci. 2015 Jan;143(1):97-106. doi: 10.1093/toxsci/kfu210. Epub 2014 Oct 10.
• [12] 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.
• [13] Transcriptome and DNA methylome dynamics during triclosan-induced cardiomyocyte differentiation toxicity. Stem Cells Int. 2018 Oct 29;2018:8608327.
• [14] MIP-1beta, a novel biomarker for in vitro sensitization test using human monocytic cell line. Toxicol In Vitro. 2006 Aug;20(5):736-42.
• [15] 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.
• [16] Activin/nodal signaling switches the terminal fate of human embryonic stem cell-derived trophoblasts. J Biol Chem. 2015 Apr 3;290(14):8834-48.