HMGA2/TET1/HOXA9 signaling pathway regulates breast cancer growth and metastasis.

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.

authors

Sun M,Song CX,Huang H,Frankenberger CA,Sankarasharma D,Gomes S,Chen P,Chen J,Chada KK,He C,Rosner MR

doi

10.1073/pnas.1305172110

subject

Has Abstract

pub_date

2013-06-11 00:00:00

pages

9920-5

issue

24

eissn

0027-8424

issn

1091-6490

pii

1305172110

journal_volume

110

pub_type

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