Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTPRKS6S)

• DOT Name: Splicing factor 3B subunit 6 (SF3B6)
• Synonyms: Pre-mRNA branch site protein p14; SF3b 14 kDa subunit; SF3B14a; Spliceosome-associated protein, 14-kDa; Splicing factor 3b, subunit 6, 14kDa
• Gene Name: SF3B6
• Related Disease:
  Adenocarcinoma
  Glioma
  Hepatocellular carcinoma
  Medulloblastoma
  Acute myelogenous leukaemia
  Acute myocardial infarction
  Advanced cancer
  Bladder cancer
  Breast neoplasm
  Clear cell renal carcinoma
  Cystic fibrosis
  Familial adenomatous polyposis
  Hepatitis B virus infection
  Hepatitis C virus infection
  Liver cirrhosis
  Lung cancer
  Lung carcinoma
  Lymphoma
  Neoplasm
  Pancreatic cancer
  Plasma cell myeloma
  Promyelocytic leukaemia
  Renal cell carcinoma
  Rheumatoid arthritis
  Schizophrenia
  Severe congenital neutropenia
  Sjogren syndrome
  Skin cancer
  Small lymphocytic lymphoma
  Small-cell lung cancer
  Squamous cell carcinoma
  Systemic lupus erythematosus
  Systemic sclerosis
  Urinary bladder cancer
  Urinary bladder neoplasm
  Breast cancer
  Breast carcinoma
  Lung adenocarcinoma
  Pediatric lymphoma
  Stroke
  Carcinoma
  Adult lymphoma
  Colorectal carcinoma
  Intellectual disability
  Melanoma
  Type-1/2 diabetes
• UniProt ID: SF3B6_HUMAN
• PDB ID: 2F9D; 2F9J; 2FHO; 3LQV; 5Z56; 5Z57; 5Z58; 6AH0; 6AHD; 6FF4; 6FF7; 6Y53; 6Y5Q; 7ABG; 7ABH; 7ABI; 7DVQ; 7Q4O
• Pfam ID: PF00076
• Sequence:
  MAMQAAKRANIRLPPEVNRILYIRNLPYKITAEEMYDIFGKYGPIRQIRVGNTPETRGTA
  YVVYEDIFDAKNACDHLSGFNVCNRYLVVLYYNANRAFQKMDTKKKEEQLKLLKEKYGIN
  TDPPK
• Function: Component of the 17S U2 SnRNP complex of the spliceosome, a large ribonucleoprotein complex that removes introns from transcribed pre-mRNAs. The 17S U2 SnRNP complex (1) directly participates in early spliceosome assembly and (2) mediates recognition of the intron branch site during pre-mRNA splicing by promoting the selection of the pre-mRNA branch-site adenosine, the nucleophile for the first step of splicing. Within the 17S U2 SnRNP complex, SF3B6 is part of the SF3B subcomplex, which is required for 'A' complex assembly formed by the stable binding of U2 snRNP to the branchpoint sequence in pre-mRNA. Sequence independent binding of SF3A and SF3B subcomplexes upstream of the branch site is essential, it may anchor U2 snRNP to the pre-mRNA. Within the 17S U2 SnRNP complex, SF3B6 directly contacts the pre-mRNA branch site adenosine for the first catalytic step of splicing. SF3B6 stabilizes the intron branch site-U2 snRNA duplex, thereby promoting-binding of introns with poor sequence complementarity. Also acts as a component of the minor spliceosome, which is involved in the splicing of U12-type introns in pre-mRNAs.
• KEGG Pathway: Spliceosome (hsa03040)
• Reactome Pathway:
  mRNA Splicing - Minor Pathway (R-HSA-72165)
  mRNA Splicing - Major Pathway (R-HSA-72163)

Molecular Interaction Atlas (MIA) of This DOT

46 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Adenocarcinoma	DIS3IHTY	Definitive	Posttranslational Modification	[1]
Glioma	DIS5RPEH	Definitive	Biomarker	[2]
Hepatocellular carcinoma	DIS0J828	Definitive	Genetic Variation	[3]
Medulloblastoma	DISZD2ZL	Definitive	Biomarker	[4]
Acute myelogenous leukaemia	DISCSPTN	Strong	Posttranslational Modification	[5]
Acute myocardial infarction	DISE3HTG	Strong	Biomarker	[6]
Advanced cancer	DISAT1Z9	Strong	Altered Expression	[7]
Bladder cancer	DISUHNM0	Strong	Posttranslational Modification	[8]
Breast neoplasm	DISNGJLM	Strong	Biomarker	[9]
Clear cell renal carcinoma	DISBXRFJ	Strong	Genetic Variation	[10]
Cystic fibrosis	DIS2OK1Q	Strong	Biomarker	[11]
Familial adenomatous polyposis	DISW53RE	Strong	Biomarker	[12]
Hepatitis B virus infection	DISLQ2XY	Strong	Biomarker	[13]
Hepatitis C virus infection	DISQ0M8R	Strong	Altered Expression	[14]
Liver cirrhosis	DIS4G1GX	Strong	Genetic Variation	[15]
Lung cancer	DISCM4YA	Strong	Posttranslational Modification	[16]
Lung carcinoma	DISTR26C	Strong	Posttranslational Modification	[16]
Lymphoma	DISN6V4S	Strong	Altered Expression	[17]
Neoplasm	DISZKGEW	Strong	Biomarker	[7]
Pancreatic cancer	DISJC981	Strong	Genetic Variation	[12]
Plasma cell myeloma	DIS0DFZ0	Strong	Posttranslational Modification	[18]
Promyelocytic leukaemia	DISYGG13	Strong	Posttranslational Modification	[5]
Renal cell carcinoma	DISQZ2X8	Strong	Genetic Variation	[10]
Rheumatoid arthritis	DISTSB4J	Strong	Altered Expression	[11]
Schizophrenia	DISSRV2N	Strong	Genetic Variation	[19]
Severe congenital neutropenia	DISES99N	Strong	Genetic Variation	[20]
Sjogren syndrome	DISUBX7H	Strong	Altered Expression	[11]
Skin cancer	DISTM18U	Strong	Genetic Variation	[21]
Small lymphocytic lymphoma	DIS30POX	Strong	Biomarker	[22]
Small-cell lung cancer	DISK3LZD	Strong	Biomarker	[23]
Squamous cell carcinoma	DISQVIFL	Strong	Biomarker	[24]
Systemic lupus erythematosus	DISI1SZ7	Strong	Altered Expression	[11]
Systemic sclerosis	DISF44L6	Strong	Altered Expression	[11]
Urinary bladder cancer	DISDV4T7	Strong	Posttranslational Modification	[8]
Urinary bladder neoplasm	DIS7HACE	Strong	Posttranslational Modification	[8]
Breast cancer	DIS7DPX1	moderate	Genetic Variation	[25]
Breast carcinoma	DIS2UE88	moderate	Genetic Variation	[25]
Lung adenocarcinoma	DISD51WR	moderate	Altered Expression	[26]
Pediatric lymphoma	DIS51BK2	moderate	Altered Expression	[17]
Stroke	DISX6UHX	moderate	Genetic Variation	[27]
Carcinoma	DISH9F1N	Disputed	Biomarker	[28]
Adult lymphoma	DISK8IZR	Limited	Altered Expression	[17]
Colorectal carcinoma	DIS5PYL0	Limited	Posttranslational Modification	[29]
Intellectual disability	DISMBNXP	Limited	Biomarker	[30]
Melanoma	DIS1RRCY	Limited	Biomarker	[31]
Type-1/2 diabetes	DISIUHAP	Limited	Genetic Variation	[32]

10 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 Splicing factor 3B subunit 6 (SF3B6).	[33]
Tretinoin	DM49DUI	Approved	Tretinoin decreases the expression of Splicing factor 3B subunit 6 (SF3B6).	[34]
Doxorubicin	DMVP5YE	Approved	Doxorubicin increases the expression of Splicing factor 3B subunit 6 (SF3B6).	[35]
Ivermectin	DMDBX5F	Approved	Ivermectin decreases the expression of Splicing factor 3B subunit 6 (SF3B6).	[36]
Nicotine	DMWX5CO	Approved	Nicotine increases the expression of Splicing factor 3B subunit 6 (SF3B6).	[37]
PMID28460551-Compound-2	DM4DOUB	Patented	PMID28460551-Compound-2 decreases the expression of Splicing factor 3B subunit 6 (SF3B6).	[40]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A decreases the expression of Splicing factor 3B subunit 6 (SF3B6).	[41]
Formaldehyde	DM7Q6M0	Investigative	Formaldehyde increases the expression of Splicing factor 3B subunit 6 (SF3B6).	[42]
Milchsaure	DM462BT	Investigative	Milchsaure increases the expression of Splicing factor 3B subunit 6 (SF3B6).	[43]
chloropicrin	DMSGBQA	Investigative	chloropicrin affects the expression of Splicing factor 3B subunit 6 (SF3B6).	[44]

2 Drug(s) Affected the Post-Translational Modifications of This DOT

Drug Name	Drug ID	Highest Status	Interaction	REF
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene affects the methylation of Splicing factor 3B subunit 6 (SF3B6).	[38]
TAK-243	DM4GKV2	Phase 1	TAK-243 increases the sumoylation of Splicing factor 3B subunit 6 (SF3B6).	[39]

References

• [1] EBV-infection in cardiac and non-cardiac gastric adenocarcinomas is associated with promoter methylation of p16, p14 and APC, but not hMLH1.Cell Oncol (Dordr). 2011 Jun;34(3):209-14. doi: 10.1007/s13402-011-0028-6. Epub 2011 May 3.
• [2] Frequent and variable abnormalities in p14 tumor suppressor gene in glioma cell lines.Brain Tumor Pathol. 2008;25(1):9-17. doi: 10.1007/s10014-007-0226-0. Epub 2008 Apr 16.
• [3] Role of P14 and MGMT gene methylation in hepatocellular carcinomas: a meta-analysis.Asian Pac J Cancer Prev. 2014;15(16):6591-6. doi: 10.7314/apjcp.2014.15.16.6591.
• [4] Frequent but borderline methylation of p16 (INK4a) and TIMP3 in medulloblastoma and sPNET revealed by quantitative analyses.J Neurooncol. 2007 May;83(1):17-29. doi: 10.1007/s11060-006-9309-8. Epub 2007 Jan 6.
• [5] Epigenetic dysregulation of the DAP kinase/p14/HDM2/p53/Apaf-1 apoptosis pathway in acute leukaemias.J Clin Pathol. 2008 Jul;61(7):844-7. doi: 10.1136/jcp.2007.047324.
• [6] Regenerative Potential of Neonatal Porcine Hearts.Circulation. 2018 Dec 11;138(24):2809-2816. doi: 10.1161/CIRCULATIONAHA.118.034886.
• [7] An Oncolytic Adenovirus Vector Expressing p14 FAST Protein Induces Widespread Syncytium Formation and Reduces Tumor Growth Rate InVivo.Mol Ther Oncolytics. 2019 May 15;14:107-120. doi: 10.1016/j.omto.2019.05.001. eCollection 2019 Sep 27.
• [8] Hypermethylation of E-cadherin, p16, p14, and RASSF1A genes in pathologically normal urothelium predict bladder recurrence of bladder cancer after transurethral resection.Urol Oncol. 2012 Mar-Apr;30(2):177-81. doi: 10.1016/j.urolonc.2010.01.002. Epub 2010 Aug 25.
• [9] Association of Mouse Mammary Tumor Virus With Human Breast Cancer: Histology, Immunohistochemistry and Polymerase Chain Reaction Analyses.Front Oncol. 2018 May 7;8:141. doi: 10.3389/fonc.2018.00141. eCollection 2018.
• [10] Major role for a 3p21 region and lack of involvement of the t(3;8) breakpoint region in the development of renal cell carcinoma suggested by loss of heterozygosity analysis.Genes Chromosomes Cancer. 1996 Jan;15(1):64-72. doi: 10.1002/(SICI)1098-2264(199601)15:1<64::AID-GCC9>3.0.CO;2-2.
• [11] Myeloid calcium binding proteins: expression in the differentiated HL-60 cells and detection in sera of patients with connective tissue diseases.J Biochem. 1990 Oct;108(4):650-3. doi: 10.1093/oxfordjournals.jbchem.a123257.
• [12] CDKN2A germline mutations in familial pancreatic cancer.Ann Surg. 2002 Dec;236(6):730-7. doi: 10.1097/00000658-200212000-00005.
• [13] Promoter hypermethylation of p14 (ARF) , RB, and INK4 gene family in hepatocellular carcinoma with hepatitis B virus infection.Tumour Biol. 2014 Mar;35(3):2795-802. doi: 10.1007/s13277-013-1372-0. Epub 2013 Nov 20.
• [14] Hepatitis C virus Core overcomes all-trans retinoic acid-induced apoptosis in human hepatoma cells by inhibiting p14 expression via DNA methylation.Oncotarget. 2017 Aug 18;8(49):85584-85598. doi: 10.18632/oncotarget.20337. eCollection 2017 Oct 17.
• [15] Studying the frequency of aberrant DNA methylation of APC, P14, and E-cadherin genes in HCV-related hepatocarcinogenesis.Cancer Biomark. 2018;22(3):503-509. doi: 10.3233/CBM-171156.
• [16] Aberrant p16 promoter methylation in smokers and former smokers with nonsmall cell lung cancer.Int J Cancer. 2003 Oct 10;106(6):913-8. doi: 10.1002/ijc.11322.
• [17] Primary malignant lymphoma of the brain: frequent abnormalities and inactivation of p14 tumor suppressor gene.Cancer Sci. 2005 Jan;96(1):38-41. doi: 10.1111/j.1349-7006.2005.00003.x.
• [18] Epigenetic dysregulation of the death-associated protein kinase/p14/HDM2/p53/Apaf-1 apoptosis pathway in multiple myeloma. J Clin Pathol. 2007 Jun;60(6):664-9. doi: 10.1136/jcp.2006.038331.
• [19] Early Development of Parvalbumin-, Somatostatin-, and Cholecystokinin-Expressing Neurons in Rat Brain following Prenatal Immune Activation and Maternal Iron Deficiency.Dev Neurosci. 2016;38(5):342-353. doi: 10.1159/000454677. Epub 2017 Feb 18.
• [20] Clinical implications of ELA2-, HAX1-, and G-CSF-receptor (CSF3R) mutations in severe congenital neutropenia.Br J Haematol. 2009 Feb;144(4):459-67. doi: 10.1111/j.1365-2141.2008.07425.x. Epub 2008 Dec 10.
• [21] p14ARF hypermethylation is common but INK4a-ARF locus or p53 mutations are rare in Merkel cell carcinoma.J Invest Dermatol. 2008 Jul;128(7):1788-96. doi: 10.1038/sj.jid.5701256. Epub 2008 Jan 24.
• [22] Frequent DAP kinase but not p14 or Apaf-1 hypermethylation in B-cell chronic lymphocytic leukemia.J Hum Genet. 2006;51(9):832-838. doi: 10.1007/s10038-006-0029-x. Epub 2006 Aug 3.
• [23] A 2.5-Mb physical map within 3p21.1 spans the breakpoint associated with Greig cephalopolysyndactyly syndrome.Genomics. 1991 Sep;11(1):93-102. doi: 10.1016/0888-7543(91)90105-n.
• [24] Frequency of genetic and epigenetic alterations of p14ARF and p16INK4A in head and neck cancer in a Hungarian population.Pathol Oncol Res. 2014 Oct;20(4):923-9. doi: 10.1007/s12253-014-9775-9. Epub 2014 Apr 9.
• [25] Promoter hypermethylation of RAR2, DAPK, hMLH1, p14, and p15 is associated with progression of breast cancer: A PRISMA-compliant meta-analysis.Medicine (Baltimore). 2018 Dec;97(51):e13666. doi: 10.1097/MD.0000000000013666.
• [26] Adenovirus-Mediated Expression of the p14 Fusion-Associated Small Transmembrane Protein Promotes Cancer Cell Fusion and Apoptosis In Vitro but Does Not Provide Therapeutic Efficacy in a Xenograft Mouse Model of Cancer.PLoS One. 2016 Mar 17;11(3):e0151516. doi: 10.1371/journal.pone.0151516. eCollection 2016.
• [27] Focal Stroke in the Developing Rat Motor Cortex Induces Age- and Experience-Dependent Maladaptive Plasticity of Corticospinal System.Front Neural Circuits. 2017 Jun 29;11:47. doi: 10.3389/fncir.2017.00047. eCollection 2017.
• [28] p14 expression differences in ovarian benign, borderline and malignant epithelial tumors.J Ovarian Res. 2016 Oct 22;9(1):69. doi: 10.1186/s13048-016-0275-2.
• [29] 18q loss of heterozygosity in microsatellite stable colorectal cancer is correlated with CpG island methylator phenotype-negative (CIMP-0) and inversely with CIMP-low and CIMP-high.BMC Cancer. 2007 May 2;7:72. doi: 10.1186/1471-2407-7-72.
• [30] Partial tetrasomy with triplication of chromosome (5) (p14-p15.33) in a patient with severe multiple congenital anomalies.Am J Med Genet. 1998 Sep 1;79(2):103-7.
• [31] Mutual exclusivity analysis of genetic and epigenetic drivers in melanoma identifies a link between p14 ARF and RAR signaling.Mol Cancer Res. 2013 Oct;11(10):1166-78. doi: 10.1158/1541-7786.MCR-13-0006. Epub 2013 Jul 12.
• [32] Islet biology, the CDKN2A/B locus and type 2 diabetes risk.Diabetologia. 2016 Aug;59(8):1579-93. doi: 10.1007/s00125-016-3967-7. Epub 2016 May 7.
• [33] A transcriptome-based classifier to identify developmental toxicants by stem cell testing: design, validation and optimization for histone deacetylase inhibitors. Arch Toxicol. 2015 Sep;89(9):1599-618.
• [34] 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.
• [35] 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.
• [36] 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.
• [37] Nicotinic modulation of gene expression in SH-SY5Y neuroblastoma cells. Brain Res. 2006 Oct 20;1116(1):39-49.
• [38] 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.
• [39] 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.
• [40] 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.
• [41] Bisphenol A induces DSB-ATM-p53 signaling leading to cell cycle arrest, senescence, autophagy, stress response, and estrogen release in human fetal lung fibroblasts. Arch Toxicol. 2018 Apr;92(4):1453-1469.
• [42] Characterization of formaldehyde's genotoxic mode of action by gene expression analysis in TK6 cells. Arch Toxicol. 2013 Nov;87(11):1999-2012.
• [43] Transcriptional profiling of lactic acid treated reconstructed human epidermis reveals pathways underlying stinging and itch. Toxicol In Vitro. 2019 Jun;57:164-173.
• [44] Transcriptomic analysis of human primary bronchial epithelial cells after chloropicrin treatment. Chem Res Toxicol. 2015 Oct 19;28(10):1926-35.