The TCF4/beta-catenin pathway and chromatin structure cooperate to regulate D-glucuronyl C5-epimerase expression in breast cancer

• D-glucuronyl C5-epimerase (GLCE) is a potential tumor-suppressor gene involved in heparan sulfate biosynthesis. GLCE expression is significantly decreased in breast tumors; however, the underlying molecular mechanisms remain unclear. This study examined the possible epigenetic mechanisms for GLCE inactivation in breast cancer. Very little methylation of the GLCE promoter region was detected in breast tumors in vivo and in breast cancer cells (MCF7 and T47D) in vitro and GLCE expression in breast cancer cells was not altered by 5-deoxyazacytidine (5-aza-dC) treatment, suggesting that promoter methylation is not involved in regulating GLCE expression. Chromatin activation by Trichostatin A (TSA) or 5-aza-dC/TSA treatment increased GLCE expression by two to 3-fold due to an increased interaction between the GLCE promoter and the TCF4/beta-catenin transactivation complex, or H3K9ac and H3K4Me3 histone modifications. However, ectopic expression of TCF4/beta-catenin was not sufficient to activate GLCE expression in MCF7 cells, suggesting that chromatin structure plays a key role in GLCE regulation. Although TSA treatment significantly repressed canonical WNT signaling in MCF7 cells, it did not influence endogenous TCF4/beta-catenin mRNA levels and activated TCF4/beta-catenin-driven transcription from the GLCE promoter, indicating GLCE as a novel target for TCF4/beta-catenin complex in breast cancer cells. A correlation was observed between GLCE, TCF4 and beta-catenin expression in breast cancer cells and primary tumors, suggesting an important role for TCF4/beta-catenin in regulating GLCE expression both in vitro and in vivo. Taken together, the results indicate that GLCE expression in breast cancer is regulated by a combination of chromatin structure and TCF4/beta-catenin complex activity.

Nyckelord

D-glucuronyl C5-epimerase

GLCE

heparan sulphate proteoglycan

biosynthesis

tumor-suppressor gene

hypermethylation

chromatin structure

WNT signaling

TCF4/beta-catenin target

breast cancer

MEDICINE

MEDICIN

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