Abstract:
:The ten-eleven translocation (TET) family of methylcytosine dioxygenases initiates demethylation of DNA and is associated with tumorigenesis in many cancers; however, the mechanism is mostly unknown. Here we identify upstream activators and downstream effectors of TET1 in breast cancer using human breast cancer cells and a genetically engineered mouse model. We show that depleting the architectural transcription factor high mobility group AT-hook 2 (HMGA2) induces TET1. TET1 binds and demethylates its own promoter and the promoter of homeobox A (HOXA) genes, enhancing its own expression and stimulating expression of HOXA genes including HOXA7 and HOXA9. Both TET1 and HOXA9 suppress breast tumor growth and metastasis in mouse xenografts. The genes comprising the HMGA2-TET1-HOXA9 pathway are coordinately regulated in breast cancer and together encompass a prognostic signature for patient survival. These results implicate the HMGA2-TET1-HOX signaling pathway in the epigenetic regulation of human breast cancer and highlight the importance of targeting methylation in specific subpopulations as a potential therapeutic strategy.
journal_name
Proc Natl Acad Sci U S Aauthors
Sun M,Song CX,Huang H,Frankenberger CA,Sankarasharma D,Gomes S,Chen P,Chen J,Chada KK,He C,Rosner MRdoi
10.1073/pnas.1305172110subject
Has Abstractpub_date
2013-06-11 00:00:00pages
9920-5issue
24eissn
0027-8424issn
1091-6490pii
1305172110journal_volume
110pub_type
杂志文章abstract::Genetic polymorphism in the H-2:Qa:Tla region of chromosome 17 is associated with constitutive variation of bodily odor phenotypes which permit individual olfactory recognition among mice. To determine whether known genes in the H-2:Qa:Tla complex are concerned in the constitution of odor phenotypes, mice were tested ...
journal_title:Proceedings of the National Academy of Sciences of the United States of America
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