TWIST represses estrogen receptor-alpha expression by recruiting the NuRD protein complex in breast cancer cells.

TitleTWIST represses estrogen receptor-alpha expression by recruiting the NuRD protein complex in breast cancer cells.
Publication TypeJournal Article
Year of Publication2012
AuthorsFu, J, Zhang, L, He, T, Xiao, X, Liu, X, Wang, L, Yang, L, Yang, M, Zhang, T, Chen, R, Xu, J
JournalInt J Biol Sci
Date Published2012
KeywordsBlotting, Western, Breast Neoplasms, Cell Line, Chromatin Immunoprecipitation, Estrogen Receptor alpha, Female, Histone Deacetylases, Humans, In Vitro Techniques, Mi-2 Nucleosome Remodeling and Deacetylase Complex, Polymerase Chain Reaction, Twist-Related Protein 1

Loss of estrogen receptor α (ERα) expression and gain of TWIST (TWIST1) expression in breast tumors correlate with increased disease recurrence and metastasis and poor disease-free survival. However, the molecular and functional regulatory relationship between TWIST and ERα are unclear. In this study, we found TWIST was associated with a chromatin region in intron 7 of the human ESR1 gene coding for ERα. This association of TWIST efficiently recruited the nucleosome remodeling and deacetylase (NuRD) repressor complex to this region, which subsequently decreased histone H3K9 acetylation, increased histone H3K9 methylation and repressed ESR1 expression in breast cancer cells. In agreement with these molecular events, TWIST expression was inversely correlated with ERα expression in both breast cancer cell lines and human breast ductal carcinomas. Forced expression of TWIST in TWIST-negative and ERα-positive breast cancer cells such as T47D and MCF-7 cells reduced ERα expression, while knockdown of TWIST in TWIST-positive and ERα-negative breast cancer cells such as MDA-MB-435 and 4T1 cells increased ERα expression. Furthermore, inhibition of histone deacetylase (HDAC) activity including the one in NuRD complex significantly increased ERα expression in MDA-MB-435 and 4T1 cells. HDAC inhibition together with TWIST knockdown did not further increase ERα expression in 4T1 and MDA-MB-435 cells. These results demonstrate that TWIST/NuRD represses ERα expression in breast cancer cells. Therefore, TWIST may serve as a potential molecular target for converting ERα-negative breast cancers to ERα-positive breast cancers, allowing these cancers to restore their sensitivity to endocrine therapy with selective ERα antagonists such as tamoxifen and raloxifene.

Alternate JournalInt J Biol Sci
PubMed ID22457607
PubMed Central IDPMC3314193
Grant ListR01 CA112403 / CA / NCI NIH HHS / United States

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