TOX3 explained

TOX high mobility group box family member 3
Hgncid:11972
Symbol:TOX3
Altsymbols:TNRC9, CAGF9
Entrezgene:27324
Omim:611416
Refseq:XM_049037
Uniprot:O15405
Chromosome:16
Arm:q
Band:12.1

TOX high mobility group box family member 3, also known as TOX3, is a human gene.[1] [2]

The protein encoded by this gene is a member of a subfamily of transcription factors that also includes TOX, TOX2, and TOX4 that share almost identical HMG-box DNA-binding domains which function to modify chromatin structure by unwinding and bending DNA.[3] The protein TOX3 has a glutamine-rich C-terminus due to CAG repeats.[4] TOX3 is located on human chromosome band 16q12.1.[5] The gene consists of seven exons and is highly expressed in both the brain and luminal epithelial breast tissue.[6] Mutations in the gene are associated with increased susceptibility to breast cancer.[2] TOX3 plays a role in regulating calcium-dependent transcription and interacts with cAMP-response-element-binding protein (CREB) and CREB-binding protein (CBP).[7] It also increases transcription via interaction with CITED1, a transcription co-regulator that increases transcription factor activity.

Disease linkage

Mutations in the TOX3 gene are associated with an increased risk of breast cancer.[2] [8] [9]

The risk allele rs3803662 is a low-penetrance SNP (single nucleotide polymorphism) associated with decreased expression of TOX3 and an increase in breast cancer risk. The risk locus was reported to regulate affinity of FOXA1 binding to chromatin, potentially affecting TOX3 expression. This locus also interacts with high-penetrance mutations BRCA1 and BRCA2 to increase risk.[10] The rs3803662 variant has a high frequency in the population, with a minor allele frequency of 0.25.[11]

Little is known of the transcriptional mechanisms and protein interactions of TOX3. However, a 2019 publication identified TOX3 as a cancer suppressor gene in clear cell renal cell carcinoma (ccRCC) and reported that downregulation of TOX3 facilitates the epithelial mesenchymal transition by decreasing repression of SNAI1 and SNAI2, resulting in tumor growth and metastasis.[12] Like breast cancer, downregulation of TOX3 is associated with worse prognosis in ccRCC patients.

Notes and References

  1. Smid M, Wang Y, Klijn JG, Sieuwerts AM, Zhang Y, Atkins D, Martens JW, Foekens JA . 6 . Genes associated with breast cancer metastatic to bone . Journal of Clinical Oncology . 24 . 15 . 2261–7 . May 2006 . 16636340 . 10.1200/JCO.2005.03.8802 .
  2. Easton DF, Pooley KA, Dunning AM, Pharoah PD, Thompson D, Ballinger DG, etal . Genome-wide association study identifies novel breast cancer susceptibility loci . Nature . 447 . 7148 . 1087–93 . June 2007 . 17529967 . 2714974 . 10.1038/nature05887 . 2007Natur.447.1087E .
  3. O'Flaherty E, Kaye J . TOX defines a conserved subfamily of HMG-box proteins . BMC Genomics . 4 . 1 . 13 . April 2003 . 12697058 . 155677 . 10.1186/1471-2164-4-13 . free .
  4. Web site: TOX3 TOX high mobility group box family member 3 [Homo sapiens (human)] ]. Gene - NCBI . National Center for Biotechnology Information (NCBI), U.S. National Library of Medicine .
  5. Web site: TOX3 (TOX high mobility group box family member 3) . Atlas of Genetics and Cytogenetics in Oncology and Haematology .
  6. Jones JO, Chin SF, Wong-Taylor LA, Leaford D, Ponder BA, Caldas C, Maia AT . TOX3 mutations in breast cancer . PLOS ONE . 8 . 9 . e74102 . 2013 . 24069272 . 3777980 . 10.1371/journal.pone.0074102 . 2013PLoSO...874102J . free .
  7. Gudmundsdottir ET, Barkardottir RB, Arason A, Gunnarsson H, Amundadottir LT, Agnarsson BA, Johannsson OT, Reynisdottir I . 6 . The risk allele of SNP rs3803662 and the mRNA level of its closest genes TOX3 and LOC643714 predict adverse outcome for breast cancer patients . BMC Cancer . 12 . 621 . December 2012 . 23270421 . 3553017 . 10.1186/1471-2407-12-621 . free .
  8. Stacey SN, Manolescu A, Sulem P, Rafnar T, Gudmundsson J, Gudjonsson SA, etal . Common variants on chromosomes 2q35 and 16q12 confer susceptibility to estrogen receptor-positive breast cancer . Nature Genetics . 39 . 7 . 865–9 . July 2007 . 17529974 . 10.1038/ng2064 . 7346190 .
  9. Antoniou AC, Spurdle AB, Sinilnikova OM, Healey S, Pooley KA, Schmutzler RK, etal . Common breast cancer-predisposition alleles are associated with breast cancer risk in BRCA1 and BRCA2 mutation carriers . American Journal of Human Genetics . 82 . 4 . 937–48 . April 2008 . 18355772 . 2427217 . 10.1016/j.ajhg.2008.02.008 .
  10. Web site: OMIM Entry - * 611416 - TOX HIGH MOBILITY GROUP BOX FAMILY MEMBER 3; TOX3 . Online Mendelian Inheritance in Man (OMIM) .
  11. Mavaddat N, Antoniou AC, Easton DF, Garcia-Closas M . Genetic susceptibility to breast cancer . Molecular Oncology . 4 . 3 . 174–91 . June 2010 . 20542480 . 5527934 . 10.1016/j.molonc.2010.04.011 .
  12. Jiang B, Chen W, Qin H, Diao W, Li B, Cao W, Zhang Z, Qi W, Gao J, Chen M, Zhao X, Guo H . 6 . TOX3 inhibits cancer cell migration and invasion via transcriptional regulation of SNAI1 and SNAI2 in clear cell renal cell carcinoma . Cancer Letters . 449 . 76–86 . May 2019 . 30772441 . 10.1016/j.canlet.2019.02.020 . 73487599 .

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