The zinc-finger transcriptional factor Slug transcriptionally downregulates ERα by recruiting lysine-specific demethylase 1 in human breast cancer

Abstract

Estrogen receptor α (ERα) is related with epithelial–mesenchymal transition, invasion and metastasis, and serves as an important therapeutic predictor and prognostic factor in breast cancer patients. The triple negative breast cancer (TNBC) is characterized by loss of hormone receptors and human epidermal growth factor receptor 2 (Her2), and lacks effective targeted therapy with poor prognosis. Unfortunately, the molecular mechanisms of ERα deficiency, which becomes hormone independent and results in resistance to endocrine therapy, remain to be elucidated in breast cancer. In this study, we observed an inverse correlation between Slug, a zinc-finger transcriptional repressor, and ERα expression in both human breast cancer tissues and cell lines. In ERα-negative breast cancer patients, high Slug messenger RNA expression showed obviously shorter relapse-free survival. We found that Slug binds to the E-box located in the promoter of estrogen receptor 1 gene (ESR1) to suppress its expression. More specifically, Slug recruits lysine-specific demethylase 1 (LSD1) to the E-box and thereby inhibits ERα expression by demethylating H3K4me2, which is evidenced by the interaction between Slug and LSD1. Moreover, the amount of H3K4me2 binding to the E-box was significantly increased after LSD1 knockdown in MDA-MB-231 cells. Functionally, the ability to proliferate, invade and metastasize was significantly suppressed after knockdown of either Slug or LSD1 alone, or both simultaneously. Taken together, these results suggest that Slug transcriptionally inhibits ERα expression by recruiting LSD1 to the ESR1 promoter in breast cancers. Thus, targeted inhibition of Slug and LSD1 may restore ERα and lead to resensitization to hormone therapy, providing a novel therapeutic strategy for ERα-negative breast cancer patients, especially for TNBC.

Crosstalk between Notch, HIF-1α and GPER in Breast Cancer EMT

“…A few years later, the same group proposed an inverse mechanism, showing that in non-invasive MCF7 cancer cells, Snail induces EMT features by directly repressing ERα expression [ 68 ]. A recent study reported a similar mechanism of ERα repression by Slug in human breast cancer [ 69 ]. Taken together, these studies suggest a mutual functional repression between Notch1 and ERα signaling in breast cancer EMT, where ERα-responsive genes (e.g., MTA3 ) would repress the expression of EMT-transcription factors laying downstream the Notch pathway.…”

Slug and E-Cadherin: Stealth Accomplices?

“…Its functional significance has yet to be determined but may be relevant for the development of luminal breast cancer (see below). Slug plays an important role in maintaining stemness in cooperation with proteins such as Sox9 and the chromatin modifier LSD1 (Guo et al, 2012 ; Phillips et al, 2014 ; Bai et al, 2017 ). In addition, Slug determines progenitor cell lineage commitment and differentiation by actively repressing the luminal cell state (Phillips and Kuperwasser, 2014 ).…”

Estrogen receptor-α-miR-1271-SNAI2 feedback loop regulates transforming growth factor-β-induced breast cancer progression

“…Aberrant expression of SNAI2 has been observed in many human cancers, including breast cancer [43]. ERα appears to downregulate SNAI2 expression by repression of SNAI2 transcription or induction of SNAI2 degradation [3]. Here, we found that SNAI2 functions as a transcriptional repressor, which depends on the E-box binding sites on the ESR1 promoter region.…”

“…ERα can both activate and repress the expression of down-stream target genes as a ligand-activated transcription factor and is a key regulator of breast cancer development and progression. In addition, ERα serves as an important prognostic factor in patients with breast cancer [3]. ERα has been identified to promote the growth of primary breast cancer, however, it can also antagonize signaling pathways that lead to epithelial-mesenchymal transition (EMT), including transforming growth factor-β (TGF-β) signaling [4, 5].…”