Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTD16B30)

• DOT Name: Septin-4 (SEPTIN4)
• Synonyms: Bradeion beta; Brain protein H5; CE5B3 beta; Cell division control-related protein 2; hCDCREL-2; Peanut-like protein 2
• Gene Name: SEPTIN4
• Related Disease:
  Bladder transitional cell carcinoma
  Malaria
  Acute lymphocytic leukaemia
  Advanced cancer
  Amyotrophic neuralgia
  Astrocytoma
  Carcinoma
  Cardiovascular disease
  Cholangiocarcinoma
  Colonic neoplasm
  Colorectal neoplasm
  Congenital contractural arachnodactyly
  Estrogen-receptor positive breast cancer
  Glioblastoma multiforme
  Head-neck squamous cell carcinoma
  Hepatocellular carcinoma
  Hypercalcaemia
  Hypopigmentation of the skin
  Neoplasm
  Osteoporosis
  Parkinson disease
  Schizophrenia
  Triple negative breast cancer
  Breast cancer
  Breast carcinoma
  Classic galactosemia
  Melanoma
  Asthma
  Childhood acute lymphoblastic leukemia
  Colorectal carcinoma
  Meckel syndrome, type 1
  Prostate cancer
  Prostate carcinoma
• UniProt ID: SEPT4_HUMAN
• PDB ID: 6WB3
• Pfam ID: PF00735
• Sequence:
  MDRSLGWQGNSVPEDRTEAGIKRFLEDTTDDGELSKFVKDFSGNASCHPPEAKTWASRPQ
  VPEPRPQAPDLYDDDLEFRPPSRPQSSDNQQYFCAPAPLSPSARPRSPWGKLDPYDSSED
  DKEYVGFATLPNQVHRKSVKKGFDFTLMVAGESGLGKSTLVNSLFLTDLYRDRKLLGAEE
  RIMQTVEITKHAVDIEEKGVRLRLTIVDTPGFGDAVNNTECWKPVAEYIDQQFEQYFRDE
  SGLNRKNIQDNRVHCCLYFISPFGHGLRPLDVEFMKALHQRVNIVPILAKADTLTPPEVD
  HKKRKIREEIEHFGIKIYQFPDCDSDEDEDFKLQDQALKESIPFAVIGSNTVVEARGRRV
  RGRLYPWGIVEVENPGHCDFVKLRTMLVRTHMQDLKDVTRETHYENYRAQCIQSMTRLVV
  KERNRNKLTRESGTDFPIPAVPPGTDPETEKLIREKDEELRRMQEMLHKIQKQMKENY
• Function: Filament-forming cytoskeletal GTPase (Probable). Pro-apoptotic protein involved in LGR5-positive intestinal stem cell and Paneth cell expansion in the intestines, via its interaction with XIAP. May also play a role in the regulation of cell fate in the intestine. Positive regulator of apoptosis involved in hematopoietic stem cell homeostasis; via its interaction with XIAP. Negative regulator of repair and hair follicle regeneration in response to injury, due to inhibition of hair follicle stem cell proliferation, potentially via its interaction with XIAP. Plays an important role in male fertility and sperm motility. During spermiogenesis, essential for the establishment of the annulus (a fibrous ring structure connecting the midpiece and the principal piece of the sperm flagellum) which is a requisite for the structural and mechanical integrity of the sperm. Involved in the migration of cortical neurons and the formation of neuron leading processes during embryonic development. Required for dopaminergic metabolism in presynaptic autoreceptors; potentially via activity as a presynaptic scaffold protein; [Isoform ARTS]: Required for the induction of cell death mediated by TGF-beta and possibly by other apoptotic stimuli. Induces apoptosis through binding and inhibition of XIAP resulting in significant reduction in XIAP levels, leading to caspase activation and cell death. Mediates the interaction between BCL2 and XIAP, thereby positively regulating the ubiquitination and degradation of BCL2 and promoting apoptosis.
• Tissue Specificity: Widely expressed in adult and fetal tissues with highest expression in adult brain (at protein level), heart, liver and adrenal gland and fetal heart, kidney, liver and lung. Expressed in presynaptic terminals of dopaminergic neurons projecting from the substantia nigra pars compacta to the striatum (at protein level) . Expressed in axonal varicosities in dopaminergic nerve terminals (at protein level) . Expressed in the putamen and in the adjacent cerebral cortex (at protein level) . Expressed in colonic crypts (at protein level) . Also expressed in colorectal cancers and malignant melanomas. Expressed in platelets.; [Isoform ARTS]: Highly expressed in the brain and heart.
• KEGG Pathway:
  Apoptosis (hsa04210)
  Apoptosis - multiple species (hsa04215)

Molecular Interaction Atlas (MIA) of This DOT

33 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Bladder transitional cell carcinoma	DISNL46A	Definitive	Altered Expression	[1]
Malaria	DISQ9Y50	Definitive	Genetic Variation	[2]
Acute lymphocytic leukaemia	DISPX75S	Strong	Biomarker	[3]
Advanced cancer	DISAT1Z9	Strong	Biomarker	[4]
Amyotrophic neuralgia	DISOTIUZ	Strong	Genetic Variation	[5]
Astrocytoma	DISL3V18	Strong	Biomarker	[6]
Carcinoma	DISH9F1N	Strong	Genetic Variation	[7]
Cardiovascular disease	DIS2IQDX	Strong	Biomarker	[8]
Cholangiocarcinoma	DIS71F6X	Strong	Biomarker	[9]
Colonic neoplasm	DISSZ04P	Strong	Genetic Variation	[10]
Colorectal neoplasm	DISR1UCN	Strong	Biomarker	[11]
Congenital contractural arachnodactyly	DISOM1K7	Strong	Biomarker	[9]
Estrogen-receptor positive breast cancer	DIS1H502	Strong	Biomarker	[12]
Glioblastoma multiforme	DISK8246	Strong	Altered Expression	[6]
Head-neck squamous cell carcinoma	DISF7P24	Strong	Biomarker	[13]
Hepatocellular carcinoma	DIS0J828	Strong	Genetic Variation	[7]
Hypercalcaemia	DISKQ2K7	Strong	Biomarker	[13]
Hypopigmentation of the skin	DIS39YKC	Strong	Biomarker	[14]
Neoplasm	DISZKGEW	Strong	Biomarker	[15]
Osteoporosis	DISF2JE0	Strong	Biomarker	[16]
Parkinson disease	DISQVHKL	Strong	Biomarker	[17]
Schizophrenia	DISSRV2N	Strong	Altered Expression	[18]
Triple negative breast cancer	DISAMG6N	Strong	Biomarker	[4]
Breast cancer	DIS7DPX1	moderate	Biomarker	[4]
Breast carcinoma	DIS2UE88	moderate	Biomarker	[4]
Classic galactosemia	DISX7P8M	moderate	Biomarker	[19]
Melanoma	DIS1RRCY	moderate	Biomarker	[20]
Asthma	DISW9QNS	Limited	Biomarker	[21]
Childhood acute lymphoblastic leukemia	DISJ5D6U	Limited	Biomarker	[3]
Colorectal carcinoma	DIS5PYL0	Limited	Altered Expression	[22]
Meckel syndrome, type 1	DIS4YWZU	Limited	Biomarker	[23]
Prostate cancer	DISF190Y	Limited	Biomarker	[24]
Prostate carcinoma	DISMJPLE	Limited	Biomarker	[24]

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 Septin-4 (SEPTIN4).	[25]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene increases the methylation of Septin-4 (SEPTIN4).	[36]

11 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 Septin-4 (SEPTIN4).	[26]
Acetaminophen	DMUIE76	Approved	Acetaminophen decreases the expression of Septin-4 (SEPTIN4).	[27]
Cisplatin	DMRHGI9	Approved	Cisplatin increases the expression of Septin-4 (SEPTIN4).	[28]
Estradiol	DMUNTE3	Approved	Estradiol decreases the expression of Septin-4 (SEPTIN4).	[29]
Arsenic trioxide	DM61TA4	Approved	Arsenic trioxide decreases the expression of Septin-4 (SEPTIN4).	[30]
Decitabine	DMQL8XJ	Approved	Decitabine affects the expression of Septin-4 (SEPTIN4).	[31]
Cocaine	DMSOX7I	Approved	Cocaine decreases the expression of Septin-4 (SEPTIN4).	[32]
Mifepristone	DMGZQEF	Approved	Mifepristone decreases the expression of Septin-4 (SEPTIN4).	[33]
Heroin diacetylmorphine	DMDBWHY	Approved	Heroin diacetylmorphine increases the expression of Septin-4 (SEPTIN4).	[34]
SNDX-275	DMH7W9X	Phase 3	SNDX-275 increases the expression of Septin-4 (SEPTIN4).	[35]
Acetaldehyde	DMJFKG4	Investigative	Acetaldehyde increases the expression of Septin-4 (SEPTIN4).	[37]

References

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• [4] The Vitamin D Analog, MART-10, Attenuates Triple Negative Breast Cancer Cells Metastatic Potential.Int J Mol Sci. 2016 Apr 21;17(4):606. doi: 10.3390/ijms17040606.
• [5] SEPT9 sequence alternations causing hereditary neuralgic amyotrophy are associated with altered interactions with SEPT4/SEPT11 and resistance to Rho/Rhotekin-signaling.Hum Mutat. 2007 Oct;28(10):1005-13. doi: 10.1002/humu.20554.
• [6] Expression of the pro-apoptotic protein ARTS in astrocytic tumors: correlation with malignancy grade and survival rate.Cancer. 2004 Dec 1;101(11):2614-21. doi: 10.1002/cncr.20675.
• [7] Mutational analysis of proapoptotic ARTS P-loop domain in common human cancers.Pathol Res Pract. 2006;202(2):67-70. doi: 10.1016/j.prp.2005.11.001. Epub 2005 Dec 22.
• [8] Septin4 as a novel binding partner of PARP1 contributes to oxidative stress induced human umbilical vein endothelial cells injure.Biochem Biophys Res Commun. 2018 Feb 5;496(2):621-627. doi: 10.1016/j.bbrc.2018.01.105.
• [9] MART-10 represses cholangiocarcinoma cell growth and high vitamin D receptor expression indicates better prognosis for cholangiocarcinoma.Sci Rep. 2017 Mar 3;7:43773. doi: 10.1038/srep43773.
• [10] Mutational analysis of P-loop domains of proapoptotic Nod1 and ARTS genes in colon carcinomas.Acta Oncol. 2006;45(1):101-2. doi: 10.1080/02841860500374497.
• [11] Impaired expression of a human septin family gene Bradeion inhibits the growth and tumorigenesis of colorectal cancer in vitro and in vivo.Cancer Gene Ther. 2002 Jun;9(6):483-8. doi: 10.1038/sj.cgt.7700460.
• [12] MART-10, a 1,25(OH)(2)D(3) Analog, Potently Represses Metastasis of ER(+) Breast Cancer Cells with VEGF-A Overexpression.Anticancer Res. 2018 Jul;38(7):3879-3887. doi: 10.21873/anticanres.12672.
• [13] MART-10, a novel vitamin D analog, inhibits head and neck squamous carcinoma cells growth through cell cycle arrest at G0/G1 with upregulation of p21 and p27 and downregulation of telomerase.J Steroid Biochem Mol Biol. 2013 Nov;138:427-34. doi: 10.1016/j.jsbmb.2013.09.002. Epub 2013 Sep 14.
• [14] Hypopigmentation associated with an adenovirus-mediated gp100/MART-1-transduced dendritic cell vaccine for metastatic melanoma.Arch Dermatol. 2002 Jun;138(6):799-802. doi: 10.1001/archderm.138.6.799.
• [15] ARTS-based anticancer therapy: taking aim at cancer stem cells.Future Oncol. 2011 Oct;7(10):1185-94. doi: 10.2217/fon.11.96.
• [16] Synthesis and biological activities of 14-epi-MART-10 and 14-epi-MART-11: implications for cancer and osteoporosis treatment.Anticancer Res. 2009 Sep;29(9):3563-9.
• [17] Modulation of ARTS and XIAP by Parkin Is Associated with Carnosic Acid Protects SH-SY5Y Cells against 6-Hydroxydopamine-Induced Apoptosis.Mol Neurobiol. 2018 Feb;55(2):1786-1794. doi: 10.1007/s12035-017-0443-4. Epub 2017 Feb 21.
• [18] Prefrontal cortex shotgun proteome analysis reveals altered calcium homeostasis and immune system imbalance in schizophrenia.Eur Arch Psychiatry Clin Neurosci. 2009 Apr;259(3):151-63. doi: 10.1007/s00406-008-0847-2. Epub 2009 Jan 22.
• [19] Fertility in classical galactosaemia, a study of N-glycan, hormonal and inflammatory gene interactions.Orphanet J Rare Dis. 2018 Sep 19;13(1):164. doi: 10.1186/s13023-018-0906-3.
• [20] Histone deacetylase inhibitor sensitizes apoptosis-resistant melanomas to cytotoxic human T lymphocytes through regulation of TRAIL/DR5 pathway.J Immunol. 2014 Apr 15;192(8):3981-9. doi: 10.4049/jimmunol.1302532. Epub 2014 Mar 17.
• [21] Physician perspectives on the burden and management of asthma in six countries: The Global Asthma Physician Survey (GAPS).BMC Pulm Med. 2017 Nov 23;17(1):153. doi: 10.1186/s12890-017-0492-5.
• [22] Characterization of tissue- and cell-type-specific expression of a novel human septin family gene, Bradeion.Biochem Biophys Res Commun. 2001 Aug 24;286(3):547-53. doi: 10.1006/bbrc.2001.5413.
• [23] Characterization of a novel gene, PNUTL2, on human chromosome 17q22-q23 and its exclusion as the Meckel syndrome gene.Genomics. 1999 Jan 1;55(1):122-5. doi: 10.1006/geno.1998.5612.
• [24] Substitution at carbon 2 of 19-nor-1,25-dihydroxyvitamin D3 with 3-hydroxypropyl group generates an analogue with enhanced chemotherapeutic potency in PC-3 prostate cancer cells.J Steroid Biochem Mol Biol. 2011 Nov;127(3-5):269-75. doi: 10.1016/j.jsbmb.2011.08.010. Epub 2011 Sep 3.
• [25] 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.
• [26] Integrative "-Omics" analysis in primary human hepatocytes unravels persistent mechanisms of cyclosporine A-induced cholestasis. Chem Res Toxicol. 2016 Dec 19;29(12):2164-2174.
• [27] Multiple microRNAs function as self-protective modules in acetaminophen-induced hepatotoxicity in humans. Arch Toxicol. 2018 Feb;92(2):845-858.
• [28] Activation of AIFM2 enhances apoptosis of human lung cancer cells undergoing toxicological stress. Toxicol Lett. 2016 Sep 6;258:227-236.
• [29] 17-Estradiol Activates HSF1 via MAPK Signaling in ER-Positive Breast Cancer Cells. Cancers (Basel). 2019 Oct 11;11(10):1533. doi: 10.3390/cancers11101533.
• [30] Identification of transcriptome signatures and biomarkers specific for potential developmental toxicants inhibiting human neural crest cell migration. Arch Toxicol. 2016 Jan;90(1):159-80.
• [31] Acute hypersensitivity of pluripotent testicular cancer-derived embryonal carcinoma to low-dose 5-aza deoxycytidine is associated with global DNA Damage-associated p53 activation, anti-pluripotency and DNA demethylation. PLoS One. 2012;7(12):e53003. doi: 10.1371/journal.pone.0053003. Epub 2012 Dec 27.
• [32] Transcriptional profiling in the human prefrontal cortex: evidence for two activational states associated with cocaine abuse. Pharmacogenomics J. 2003;3(1):27-40.
• [33] Mifepristone induced progesterone withdrawal reveals novel regulatory pathways in human endometrium. Mol Hum Reprod. 2007 Sep;13(9):641-54.
• [34] Distinctive profiles of gene expression in the human nucleus accumbens associated with cocaine and heroin abuse. Neuropsychopharmacology. 2006 Oct;31(10):2304-12. doi: 10.1038/sj.npp.1301089. Epub 2006 May 3.
• [35] 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.
• [36] 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.
• [37] Transcriptome profile analysis of saturated aliphatic aldehydes reveals carbon number-specific molecules involved in pulmonary toxicity. Chem Res Toxicol. 2014 Aug 18;27(8):1362-70.