Abstract
The epithelial-to-mesenchymal transition (EMT) and its reversion (MET) are related to tumor cell dissemination and migration, tumor circulating cell generation, cancer stem cells, chemoresistance, and metastasis formation. To identify chromatin and epigenetic factors possibly involved in the process of EMT, we compare the levels of expression of epigenetic genes in a transformed human breast epithelial cell line (HMEC-RAS) versus a stable clone of the same cell line expressing the EMT master regulator ZEB1 (HMEC-RAS-ZEB1). One of the factors strongly induced in the HMEC-RAS-ZEB1 cells was Transducin beta-like 1 (TBL1), a component of the NCoR complex, which has both corepressor and coactivator activities. We show that TBL1 interacts with ZEB1 and that both factors cooperate to repress the promoter of the epithelial gene E-cadherin (CDH1) and to autoactivate the ZEB1 promoter. Consistent with its central role, TBL1 is required for mesenchymal phenotypes of transformed breast epithelial and breast cancer cell lines of the claudin-low subtype. Importantly, a high expression of the TBL1 gene correlates with poor prognosis and increased proportion of metastasis in breast cancer patients, indicating that the level of TBL1 expression can be used as a prognostic marker.
Highlights
Epithelial and mesenchymal cellular phenotypes are the edges of a spectrum of states that can be transitory or stable[1]
HMEC-RASZEB1 cells exhibit the transcriptional signature of claudin-low tumors, including low expression of tight and adherens junction genes, mesenchymal traits, and stem cell-like characteristics[22]
RNA-seq and clinicopathological data of the breast invasive carcinoma. In this manuscript, we analyze a number of chromatin and epigenetic factors that are upregulated in a mesenchymal transformed cell lines with respect to its parental epithelial counterpart
Summary
Epithelial and mesenchymal cellular phenotypes are the edges of a spectrum of states that can be transitory or stable[1]. Identifying epigenetic and chromatin regulators involved in EMT and MET is of paramount importance for better understanding the mechanisms responsible for tumor cell dissemination and metastasis formation, as well as for identifying putative druggable targets. With this purpose, we analyzed previously published expression data of a RAS-transformed human mammary epithelial cell line (HMEC-RAS) versus a stable clone of the same cell line expressing ZEB1 and with a strong mesenchymal phenotype (HMEC-RAS-ZEB1)[22]. Human breast cancer tumors with high expression of the TBL1 gene correlates with poor prognosis and an increased proportion of metastasis
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