Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTNCW8RJ)

• DOT Name: Testis anion transporter 1 (SLC26A8)
• Synonyms: Anion exchange transporter; Solute carrier family 26 member 8
• Gene Name: SLC26A8
• Related Disease:
  Advanced cancer
  Bladder cancer
  Carcinoma
  Cataract
  Hereditary spherocytosis
  Male infertility
  Neoplasm
  Prostate cancer
  Prostate carcinoma
  Schizophrenia
  Urinary bladder cancer
  Urinary bladder neoplasm
  Bladder transitional cell carcinoma
  Obsolete non-syndromic male infertility due to sperm motility disorder
  Follicular lymphoma
  Nervous system disease
  Spermatogenic failure 3
• UniProt ID: S26A8_HUMAN
• Pfam ID: PF01740 ; PF00916
• Sequence:
  MAQLERSAISGFSSKSRRNSFAYDVKREVYNEETFQQEHKRKASSSGNMNINITTFRHHV
  QCRCSWHRFLRCVLTIFPFLEWMCMYRLKDWLLGDLLAGISVGLVQVPQGLTLSLLARQL
  IPPLNIAYAAFCSSVIYVIFGSCHQMSIGSFFLVSALLINVLKVSPFNNGQLVMGSFVKN
  EFSAPSYLMGYNKSLSVVATTTFLTGIIQLIMGVLGLGFIATYLPESAMSAYLAAVALHI
  MLSQLTFIFGIMISFHAGPISFFYDIINYCVALPKANSTSILVFLTVVVALRINKCIRIS
  FNQYPIEFPMELFLIIGFTVIANKISMATETSQTLIDMIPYSFLLPVTPDFSLLPKIILQ
  AFSLSLVSSFLLIFLGKKIASLHNYSVNSNQDLIAIGLCNVVSSFFRSCVFTGAIARTII
  QDKSGGRQQFASLVGAGVMLLLMVKMGHFFYTLPNAVLAGIILSNVIPYLETISNLPSLW
  RQDQYDCALWMMTFSSSIFLGLDIGLIISVVSAFFITTVRSHRAKILLLGQIPNTNIYRS
  INDYREIITIPGVKIFQCCSSITFVNVYYLKHKLLKEVDMVKVPLKEEEIFSLFNSSDTN
  LQGGKICRCFCNCDDLEPLPRILYTERFENKLDPEASSINLIHCSHFESMNTSQTASEDQ
  VPYTVSSVSQKNQGQQYEEVEEVWLPNNSSRNSSPGLPDVAESQGRRSLIPYSDASLLPS
  VHTIILDFSMVHYVDSRGLVVLRQICNAFQNANILILIAGCHSSIVRAFERNDFFDAGIT
  KTQLFLSVHDAVLFALSRKVIGSSELSIDESETVIRETYSETDKNDNSRYKMSSSFLGSQ
  KNVSPGFIKIQQPVEEESELDLELESEQEAGLGLDLDLDRELEPEMEPKAETETKTQTEM
  EPQPETEPEMEPNPKSRPRAHTFPQQRYWPMYHPSMASTQSQTQTRTWSVERRRHPMDSY
  SPEGNSNEDV
• Function: Antiporter that mediates the exchange of sulfate and oxalate against chloride ions across a membrane. Stimulates anion transport activity of CFTR. May cooperate with CFTR in the regulation of chloride and bicarbonate ions fluxes required for activation of the ADCY10/PKA pathway during sperm motility and sperm capacitation. May play a role in sperm tail differentiation and motility and hence male fertility.
• Tissue Specificity: Expression observed exclusively in testis, restricted to the meiotic phase of the germ cell . Abundant expression located in the seminiferous tubules, concentrated on the luminal side of the tubuli harboring the spermatocytes and spermatids .

Molecular Interaction Atlas (MIA) of This DOT

17 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Advanced cancer	DISAT1Z9	Strong	Biomarker	[1]
Bladder cancer	DISUHNM0	Strong	Altered Expression	[2]
Carcinoma	DISH9F1N	Strong	Biomarker	[3]
Cataract	DISUD7SL	Strong	Biomarker	[4]
Hereditary spherocytosis	DISQYJP5	Strong	Genetic Variation	[5]
Male infertility	DISY3YZZ	Strong	Genetic Variation	[6]
Neoplasm	DISZKGEW	Strong	Biomarker	[7]
Prostate cancer	DISF190Y	Strong	Biomarker	[8]
Prostate carcinoma	DISMJPLE	Strong	Biomarker	[8]
Schizophrenia	DISSRV2N	Strong	Biomarker	[9]
Urinary bladder cancer	DISDV4T7	Strong	Altered Expression	[2]
Urinary bladder neoplasm	DIS7HACE	Strong	Altered Expression	[2]
Bladder transitional cell carcinoma	DISNL46A	moderate	Biomarker	[7]
Obsolete non-syndromic male infertility due to sperm motility disorder	DISG7641	Supportive	Autosomal recessive	[10]
Follicular lymphoma	DISVEUR6	Limited	Biomarker	[11]
Nervous system disease	DISJ7GGT	Limited	Biomarker	[12]
Spermatogenic failure 3	DISHSSMC	Limited	Autosomal dominant	[13]

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 increases the methylation of Testis anion transporter 1 (SLC26A8).	[14]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A decreases the methylation of Testis anion transporter 1 (SLC26A8).	[15]

References

• [1] DNA cytometric features in biopsies of TaT1 urothelial cell cancer predict recurrence and stage progression more accurately than stage, grade, or treatment modality.Urology. 2003 Jun;61(6):1266-72. doi: 10.1016/s0090-4295(03)00024-4.
• [2] Increased BCL2L12 expression predicts the short-term relapse of patients with TaT1 bladder cancer following transurethral resection of bladder tumors.Urol Oncol. 2014 Jan;32(1):39.e29-36. doi: 10.1016/j.urolonc.2013.04.005. Epub 2013 Jun 18.
• [3] Proliferation markers and DNA content analysis in urinary bladder TaT1 urothelial cell carcinomas: identification of subgroups with low and high stage progression risks.J Clin Pathol. 2003 Jun;56(6):447-52. doi: 10.1136/jcp.56.6.447.
• [4] Dysfunctional LAT2 Amino Acid Transporter Is Associated With Cataract in Mouse and Humans.Front Physiol. 2019 Jun 4;10:688. doi: 10.3389/fphys.2019.00688. eCollection 2019.
• [5] Hereditary spherocytosis (HS) due to loss of anion exchange transporter.Haematologica. 1992 Nov-Dec;77(6):450-6.
• [6] Mutational analysis of the human SLC26A8 gene: exclusion as a candidate for male infertility due to primary spermatogenic failure.Mol Hum Reprod. 2005 Feb;11(2):129-32. doi: 10.1093/molehr/gah140. Epub 2004 Dec 3.
• [7] Association of PAX5 expression with clinical outcome in patients with TaT1 transitional cell carcinoma of the bladder.Urology. 2006 Apr;67(4):756-61. doi: 10.1016/j.urology.2005.10.053. Epub 2006 Mar 29.
• [8] Expression of tumor-associated trypsinogens (TAT-1 and TAT-2) in prostate cancer.Prostate. 2005 Jun 15;64(1):29-39. doi: 10.1002/pros.20236.
• [9] Exome sequencing supports a de novo mutational paradigm for schizophrenia.Nat Genet. 2011 Aug 7;43(9):864-8. doi: 10.1038/ng.902.
• [10] Missense mutations in SLC26A8, encoding a sperm-specific activator of CFTR, are associated with human asthenozoospermia. Am J Hum Genet. 2013 May 2;92(5):760-6. doi: 10.1016/j.ajhg.2013.03.016. Epub 2013 Apr 11.
• [11] Establishment and comprehensive analysis of a new human transformed follicular lymphoma B cell line, Tat-1.Leukemia. 2002 Feb;16(2):276-83. doi: 10.1038/sj.leu.2402372.
• [12] Human immunodeficiency virus type-1 protein Tat induces tumor necrosis factor-alpha-mediated neurotoxicity.Neurobiol Dis. 2007 Jun;26(3):661-70. doi: 10.1016/j.nbd.2007.03.004. Epub 2007 Mar 20.
• [13] The testis anion transporter 1 (Slc26a8) is required for sperm terminal differentiation and male fertility in the mouse. Hum Mol Genet. 2007 Aug 1;16(15):1783-93. doi: 10.1093/hmg/ddm117. Epub 2007 May 20.
• [14] 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.
• [15] DNA methylome-wide alterations associated with estrogen receptor-dependent effects of bisphenols in breast cancer. Clin Epigenetics. 2019 Oct 10;11(1):138. doi: 10.1186/s13148-019-0725-y.