Details of Drug Off-Target (DOT)

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

• DOT Name: Serine/arginine-rich splicing factor 6 (SRSF6)
• Synonyms: Pre-mRNA-splicing factor SRP55; Splicing factor, arginine/serine-rich 6
• Gene Name: SRSF6
• Related Disease:
  Advanced cancer
  Alzheimer disease
  Autosomal dominant vitreoretinochoroidopathy
  Colon cancer
  Colon carcinoma
  Colorectal carcinoma
  Estrogen-receptor positive breast cancer
  Gastric cancer
  Huntington disease
  Hutchinson-Gilford progeria syndrome
  Metastatic malignant neoplasm
  Neoplasm
  Neuroblastoma
  Schizophrenia
  Skin cancer
  Stomach cancer
  Vitelliform macular dystrophy
  X-linked reticulate pigmentary disorder
  Breast neoplasm
  Breast cancer
  Breast carcinoma
  Type-1/2 diabetes
• UniProt ID: SRSF6_HUMAN
• Pfam ID: PF00076
• Sequence:
  MPRVYIGRLSYNVREKDIQRFFSGYGRLLEVDLKNGYGFVEFEDSRDADDAVYELNGKEL
  CGERVIVEHARGPRRDRDGYSYGSRSGGGGYSSRRTSGRDKYGPPVRTEYRLIVENLSSR
  CSWQDLKDFMRQAGEVTYADAHKERTNEGVIEFRSYSDMKRALDKLDGTEINGRNIRLIE
  DKPRTSHRRSYSGSRSRSRSRRRSRSRSRRSSRSRSRSISKSRSRSRSRSKGRSRSRSKG
  RKSRSKSKSKPKSDRGSHSHSRSRSKDEYEKSRSRSRSRSPKENGKGDIKSKSRSRSQSR
  SNSPLPVPPSKARSVSPPPKRATSRSRSRSRSKSRSRSRSSSRD
• Function: Plays a role in constitutive splicing and modulates the selection of alternative splice sites. Plays a role in the alternative splicing of MAPT/Tau exon 10. Binds to alternative exons of TNC pre-mRNA and promotes the expression of alternatively spliced TNC. Plays a role in wound healing and in the regulation of keratinocyte differentiation and proliferation via its role in alternative splicing.
• KEGG Pathway:
  Spliceosome (hsa03040)
  Herpes simplex virus 1 infection (hsa05168)
• Reactome Pathway:
  mRNA Splicing - Major Pathway (R-HSA-72163)
  mRNA Splicing - Minor Pathway (R-HSA-72165)
  mRNA 3'-end processing (R-HSA-72187)
  Processing of Capped Intron-Containing Pre-mRNA (R-HSA-72203)
  RNA Polymerase II Transcription Termination (R-HSA-73856)
  Transport of Mature mRNA derived from an Intron-Containing Transcript (R-HSA-159236)

Molecular Interaction Atlas (MIA) of This DOT

22 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Advanced cancer	DISAT1Z9	Strong	Biomarker	[1]
Alzheimer disease	DISF8S70	Strong	Biomarker	[2]
Autosomal dominant vitreoretinochoroidopathy	DISXZJ1T	Strong	Biomarker	[3]
Colon cancer	DISVC52G	Strong	Biomarker	[4]
Colon carcinoma	DISJYKUO	Strong	Biomarker	[4]
Colorectal carcinoma	DIS5PYL0	Strong	Altered Expression	[1]
Estrogen-receptor positive breast cancer	DIS1H502	Strong	Altered Expression	[5]
Gastric cancer	DISXGOUK	Strong	Altered Expression	[6]
Huntington disease	DISQPLA4	Strong	Biomarker	[7]
Hutchinson-Gilford progeria syndrome	DISY55BU	Strong	Biomarker	[8]
Metastatic malignant neoplasm	DIS86UK6	Strong	Altered Expression	[9]
Neoplasm	DISZKGEW	Strong	Altered Expression	[4]
Neuroblastoma	DISVZBI4	Strong	Biomarker	[7]
Schizophrenia	DISSRV2N	Strong	Altered Expression	[10]
Skin cancer	DISTM18U	Strong	Altered Expression	[9]
Stomach cancer	DISKIJSX	Strong	Altered Expression	[6]
Vitelliform macular dystrophy	DISEFYYN	Strong	Biomarker	[3]
X-linked reticulate pigmentary disorder	DIS0RB5A	Strong	Genetic Variation	[11]
Breast neoplasm	DISNGJLM	Disputed	Altered Expression	[5]
Breast cancer	DIS7DPX1	Limited	Biomarker	[12]
Breast carcinoma	DIS2UE88	Limited	Biomarker	[12]
Type-1/2 diabetes	DISIUHAP	Limited	Biomarker	[13]

5 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 Serine/arginine-rich splicing factor 6 (SRSF6).	[14]
TAK-243	DM4GKV2	Phase 1	TAK-243 decreases the sumoylation of Serine/arginine-rich splicing factor 6 (SRSF6).	[28]
Coumarin	DM0N8ZM	Investigative	Coumarin increases the phosphorylation of Serine/arginine-rich splicing factor 6 (SRSF6).	[30]
Paraquat	DMR8O3X	Investigative	Paraquat increases the phosphorylation of Serine/arginine-rich splicing factor 6 (SRSF6).	[32]
leucettine L41	DMBYND6	Investigative	leucettine L41 decreases the phosphorylation of Serine/arginine-rich splicing factor 6 (SRSF6).	[33]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Ciclosporin	DMAZJFX	Approved	Ciclosporin decreases the expression of Serine/arginine-rich splicing factor 6 (SRSF6).	[15]
Tretinoin	DM49DUI	Approved	Tretinoin increases the expression of Serine/arginine-rich splicing factor 6 (SRSF6).	[16]
Cupric Sulfate	DMP0NFQ	Approved	Cupric Sulfate increases the expression of Serine/arginine-rich splicing factor 6 (SRSF6).	[17]
Ivermectin	DMDBX5F	Approved	Ivermectin decreases the expression of Serine/arginine-rich splicing factor 6 (SRSF6).	[18]
Progesterone	DMUY35B	Approved	Progesterone decreases the expression of Serine/arginine-rich splicing factor 6 (SRSF6).	[19]
Niclosamide	DMJAGXQ	Approved	Niclosamide decreases the expression of Serine/arginine-rich splicing factor 6 (SRSF6).	[20]
Ethanol	DMDRQZU	Approved	Ethanol decreases the expression of Serine/arginine-rich splicing factor 6 (SRSF6).	[21]
Testosterone enanthate	DMB6871	Approved	Testosterone enanthate affects the expression of Serine/arginine-rich splicing factor 6 (SRSF6).	[22]
Piroxicam	DMTK234	Approved	Piroxicam decreases the expression of Serine/arginine-rich splicing factor 6 (SRSF6).	[23]
Indomethacin	DMSC4A7	Approved	Indomethacin decreases the expression of Serine/arginine-rich splicing factor 6 (SRSF6).	[24]
Curcumin	DMQPH29	Phase 3	Curcumin increases the expression of Serine/arginine-rich splicing factor 6 (SRSF6).	[25]
(+)-JQ1	DM1CZSJ	Phase 1	(+)-JQ1 decreases the expression of Serine/arginine-rich splicing factor 6 (SRSF6).	[26]
Leflunomide	DMR8ONJ	Phase 1 Trial	Leflunomide decreases the expression of Serine/arginine-rich splicing factor 6 (SRSF6).	[27]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A decreases the expression of Serine/arginine-rich splicing factor 6 (SRSF6).	[29]
methyl p-hydroxybenzoate	DMO58UW	Investigative	methyl p-hydroxybenzoate decreases the expression of Serine/arginine-rich splicing factor 6 (SRSF6).	[31]

References

• [1] SRSF6-regulated alternative splicing that promotes tumour progression offers a therapy target for colorectal cancer.Gut. 2019 Jan;68(1):118-129. doi: 10.1136/gutjnl-2017-314983. Epub 2017 Nov 7.
• [2] Intranasal Administration of miR-146a Agomir Rescued the Pathological Process and Cognitive Impairment in an AD Mouse Model.Mol Ther Nucleic Acids. 2019 Dec 6;18:681-695. doi: 10.1016/j.omtn.2019.10.002. Epub 2019 Oct 10.
• [3] ADVIRC is caused by distinct mutations in BEST1 that alter pre-mRNA splicing. J Med Genet. 2009 Sep;46(9):620-5. doi: 10.1136/jmg.2008.059881. Epub 2008 Jul 8.
• [4] The splicing factor SRSF6 is amplified and is an oncoprotein inlung and colon cancers.J Pathol. 2013 Mar;229(4):630-9. doi: 10.1002/path.4129.
• [5] Estrogen alters the splicing of type 1 corticotropin-releasing hormone receptor in breast cancer cells.Sci Signal. 2013 Jul 2;6(282):ra53. doi: 10.1126/scisignal.2003926.
• [6] Comparative expression patterns and diagnostic efficacies of SR splicing factors and HNRNPA1 in gastric and colorectal cancer.BMC Cancer. 2016 Jun 10;16:358. doi: 10.1186/s12885-016-2387-x.
• [7] MAP2 Splicing is Altered in Huntington's Disease.Brain Pathol. 2017 Mar;27(2):181-189. doi: 10.1111/bpa.12387. Epub 2016 Jul 7.
• [8] A conserved splicing mechanism of the LMNA gene controls premature aging.Hum Mol Genet. 2011 Dec 1;20(23):4540-55. doi: 10.1093/hmg/ddr385. Epub 2011 Aug 29.
• [9] Splicing factor SRSF6 promotes hyperplasia of sensitized skin.Nat Struct Mol Biol. 2014 Feb;21(2):189-97. doi: 10.1038/nsmb.2756. Epub 2014 Jan 19.
• [10] 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.
• [11] Splicing factor polymorphisms, the control of VEGF isoforms and association with angiogenic eye disease.Curr Eye Res. 2011 Apr;36(4):328-35. doi: 10.3109/02713683.2010.548892. Epub 2011 Feb 10.
• [12] circFBXL5 promotes breast cancer progression by sponging miR-660.J Cell Mol Med. 2020 Jan;24(1):356-361. doi: 10.1111/jcmm.14737. Epub 2019 Nov 15.
• [13] SRp55 Regulates a Splicing Network That Controls Human Pancreatic -Cell Function and Survival.Diabetes. 2018 Mar;67(3):423-436. doi: 10.2337/db17-0736. Epub 2017 Dec 15.
• [14] 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.
• [15] Comparison of HepG2 and HepaRG by whole-genome gene expression analysis for the purpose of chemical hazard identification. Toxicol Sci. 2010 May;115(1):66-79.
• [16] Pharmacogenomic analysis of acute promyelocytic leukemia cells highlights CYP26 cytochrome metabolism in differential all-trans retinoic acid sensitivity. Blood. 2007 May 15;109(10):4450-60.
• [17] Physiological and toxicological transcriptome changes in HepG2 cells exposed to copper. Physiol Genomics. 2009 Aug 7;38(3):386-401.
• [18] Quantitative proteomics reveals a broad-spectrum antiviral property of ivermectin, benefiting for COVID-19 treatment. J Cell Physiol. 2021 Apr;236(4):2959-2975. doi: 10.1002/jcp.30055. Epub 2020 Sep 22.
• [19] Gene expression in endometrial cancer cells (Ishikawa) after short time high dose exposure to progesterone. Steroids. 2008 Jan;73(1):116-28.
• [20] Mitochondrial Uncoupling Induces Epigenome Remodeling and Promotes Differentiation in Neuroblastoma. Cancer Res. 2023 Jan 18;83(2):181-194. doi: 10.1158/0008-5472.CAN-22-1029.
• [21] Gene expression signatures after ethanol exposure in differentiating embryoid bodies. Toxicol In Vitro. 2018 Feb;46:66-76.
• [22] Transcriptional profiling of testosterone-regulated genes in the skeletal muscle of human immunodeficiency virus-infected men experiencing weight loss. J Clin Endocrinol Metab. 2007 Jul;92(7):2793-802. doi: 10.1210/jc.2006-2722. Epub 2007 Apr 17.
• [23] Apoptosis induced by piroxicam plus cisplatin combined treatment is triggered by p21 in mesothelioma. PLoS One. 2011;6(8):e23569.
• [24] Mechanisms of indomethacin-induced alterations in the choline phospholipid metabolism of breast cancer cells. Neoplasia. 2006 Sep;8(9):758-71.
• [25] Gene-expression profiling during curcumin-induced apoptosis reveals downregulation of CXCR4. Exp Hematol. 2007 Jan;35(1):84-95.
• [26] Bromodomain-containing protein 4 (BRD4) regulates RNA polymerase II serine 2 phosphorylation in human CD4+ T cells. J Biol Chem. 2012 Dec 14;287(51):43137-55.
• [27] Endoplasmic reticulum stress and MAPK signaling pathway activation underlie leflunomide-induced toxicity in HepG2 Cells. Toxicology. 2017 Dec 1;392:11-21.
• [28] Inhibiting ubiquitination causes an accumulation of SUMOylated newly synthesized nuclear proteins at PML bodies. J Biol Chem. 2019 Oct 18;294(42):15218-15234. doi: 10.1074/jbc.RA119.009147. Epub 2019 Jul 8.
• [29] Alternatives for the worse: Molecular insights into adverse effects of bisphenol a and substitutes during human adipocyte differentiation. Environ Int. 2021 Nov;156:106730. doi: 10.1016/j.envint.2021.106730. Epub 2021 Jun 27.
• [30] Quantitative phosphoproteomics reveal cellular responses from caffeine, coumarin and quercetin in treated HepG2 cells. Toxicol Appl Pharmacol. 2022 Aug 15;449:116110. doi: 10.1016/j.taap.2022.116110. Epub 2022 Jun 7.
• [31] Transcriptome dynamics of alternative splicing events revealed early phase of apoptosis induced by methylparaben in H1299 human lung carcinoma cells. Arch Toxicol. 2020 Jan;94(1):127-140. doi: 10.1007/s00204-019-02629-w. Epub 2019 Nov 20.
• [32] Paraquat modulates alternative pre-mRNA splicing by modifying the intracellular distribution of SRPK2. PLoS One. 2013 Apr 16;8(4):e61980. doi: 10.1371/journal.pone.0061980. Print 2013.
• [33] Leucettines, a class of potent inhibitors of cdc2-like kinases and dual specificity, tyrosine phosphorylation regulated kinases derived from the marine sponge leucettamine B: modulation of alternative pre-RNA splicing. J Med Chem. 2011 Jun 23;54(12):4172-86.