Abstract
Aberrant estrogen receptor-α (ERα) signaling is recognized as a major contributor to the development of breast cancer. However, the molecular mechanism underlying the regulation of ERα in breast cancer is still inconclusive. In this study, we showed that the transcription factor 21 (TCF21) interacted with ERα, and repressed its transcriptional activity in a HDACs-dependent manner. We also showed that TCF21 could be sumoylated by the small ubiquitin-like modifier SUMO1, and this modification could be reversed by SENP1. Sumoylation of TCF21 occurred at lysine residue 24 (K24). Substitution of K24 with arginine resulted in complete abolishment of sumoylation. Sumoylation stabilized TCF21, but did not affect its subcellular localization. Sumoylation of TCF21 also enhanced its interaction with HDAC1/2 without affecting its interaction with ERα. Moreover, sumoylation of TCF21 promoted its repression of ERα transcriptional activity, and increased the recruitment of HDAC1/2 to the pS2 promoter. Consistent with these observations, sumoylation of TCF21 could inhibit the growth of ERα-positive breast cancer cells and decreased the proportion of S-phase cells in the cell cycle. These findings suggested that TCF21 might act as a negative regulator of ERα, and its sumoylation inhibited the transcriptional activity of ERα through promoting the recruitment of HDAC1/2.
Highlights
Breast cancer is the most frequently diagnosed malignant tumor and the leading cause of cancer related death in women worldwide [1]
transcription factor 21 (TCF21) is a member of bHLH family of transcription factors, and it has been reported to interact with androgen receptor (AR) and inhibit its function [28]
Further insight into the detailed mechanism involved in the regulation of estrogen receptor-α (ERα) function is important for us to understand the pathogenesis of ERα-positive breast cancer, and to facilitate the development of more effective breast cancer treatment strategies
Summary
Breast cancer is the most frequently diagnosed malignant tumor and the leading cause of cancer related death in women worldwide [1]. The incidence rate of breast cancer is gradually increasing due to changes in reproductive factors and increased screening intensity [2]. The occurrence of breast cancer is contributed by multiple factors, such as family history, reproductive factors, lifestyle, alcohol consumption and exposure to estrogen [3,4,5,6]. The receptors dimerize and bind to DNA at the estrogen response elements (EREs) of downstream target genes and associate with coactivators or corepressors to regulate the expression of these genes. ERα is associated with tumor initiation and development in 70–80% of breast-cancer patients [9]. ERα is considered as a good prognostic factor in breast cancer and a major target for endocrine therapy [10]
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