The TCF4/β-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/β-catenin transactivation complex, or H3K9ac and H3K4Me3 histone modifications. However, ectopic expression of TCF4/β-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/β-catenin mRNA levels and activated TCF4/β-catenin-driven transcription from the GLCE promoter, indicating GLCE as a novel target for TCF4/β-catenin complex in breast cancer cells. A correlation was observed between GLCE, TCF4 and β-catenin expression in breast cancer cells and primary tumors, suggesting an important role for TCF4/β-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/β-catenin complex activity.
Institute of Molecular Biology and Biophysics SB RAMS, Novosibirsk, Russia.
Luydmila A
LA
Mostovich
Tatiana Y
TY
Prudnikova
Aleksandr G
AG
Kondratov
Natalya V
NV
Gubanova
Olga A
OA
Kharchenko
Olesya S
OS
Kutsenko
Pavel V
PV
Vavilov
Klas
K
Haraldson
Vladimir I
VI
Kashuba
Ingemar
I
Ernberg
Eugene R
ER
Zabarovsky
Elvira V
EV
Grigorieva
D000964:Antimetabolites, Antineoplastic / Q000494:pharmacology; D001374:Azacitidine / Q000031:analogs & derivatives / Q000494:pharmacology; D051778:Basic Helix-Loop-Helix Leucine Zipper Transcription Factors / Q000378:metabolism*; D001943:Breast Neoplasms / Q000201:enzymology / Q000235:genetics* / Q000378:metabolism; D002238:Carbohydrate Epimerases / Q000235:genetics* / Q000378:metabolism; D002843:Chromatin / Q000737:chemistry / Q000378:metabolism*; D019175:DNA Methylation; D000077209:Decitabine; D044127:Epigenesis, Genetic / Q000187:drug effects / Q000235:genetics; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D056572:Histone Deacetylase Inhibitors / Q000494:pharmacology; D006657:Histones / Q000378:metabolism; D006801:Humans; D006877:Hydroxamic Acids / Q000494:pharmacology; D061986:MCF-7 Cells; D011401:Promoter Regions, Genetic; D011499:Protein Processing, Post-Translational; D000073940:Transcription Factor 4; D014157:Transcription Factors / Q000378:metabolism*; D014158:Transcription, Genetic; D060449:Wnt Signaling Pathway; D051176:beta Catenin / Q000378:metabolism*
D000964:Antimetabolites, Antineoplastic; D051778:Basic Helix-Loop-Helix Leucine Zipper Transcription Factors; C495270:CTNNB1 protein, human; D002843:Chromatin; D056572:Histone Deacetylase Inhibitors; D006657:Histones; D006877:Hydroxamic Acids; C532096:TCF4 protein, human; D000073940:Transcription Factor 4; D014157:Transcription Factors; D051176:beta Catenin; C012589:trichostatin A; D000077209:Decitabine; D002238:Carbohydrate Epimerases; C019591:heparosan N-sulfate D-glucuronosyl 5-epimerase; D001374:Azacitidine