Abstract
Ring1b is a core subunit of polycomb repressive complex 1 (PRC1) and is essential in several high-risk cancers. However, the epigenetic mechanism of Ring1b underlying breast cancer malignancy is poorly understood. In this study, we showed increased expression of Ring1b promoted metastasis by weakening cell–cell adhesions of breast cancer cells. We confirmed that Ring1b could downregulate E-cadherin and contributed to an epigenetic rewiring via PRC1-dependent function by forming distinct complexes with DEAD-box RNA helicases (DDXs) or epithelial-mesenchymal transition transcription factors (EMT TFs) on site-specific loci of E-cadherin promoter. DDXs-Ring1b complexes moderately inhibited E-cadherin, which resulted in an early hybrid EMT state of epithelial cells, and EMT TFs-Ring1b complexes cooperated with DDXs-Ring1b complexes to further repress E-cadherin in mesenchymal-like cancer cells. Clinically, high expression of Ring1b with DDXs or EMT TFs predicted low levels of E-cadherin, metastatic behavior, and poor prognosis. These findings provide an epigenetic regulation mechanism of Ring1b complexes in E-cadherin expression. Ring1b complexes may be potential therapeutic targets and biomarkers for diagnosis and prognosis in invasion breast cancer.
Highlights
Breast cancer is the second leading cause of cancer death in women, and metastasis is widely accepted as the major reason for cancer mortality[1,2]
We have found that DEAD-box RNA helicases (DDXs) (DDX3X/DDX5) or epithelialmesenchymal transition (EMT) transcription factors (EMT TFs) (Snail1/Twist2) selectively decided the recruitment and distribution of Ring1b complexes on site-specific loci of E-cadherin promoter in various EMT states cells
Our findings raise the possibility that targeting Ring1b complexes may provide a means of eliminating metastasis in breast cancer
Summary
Breast cancer is the second leading cause of cancer death in women, and metastasis is widely accepted as the major reason for cancer mortality[1,2]. The silencing of E-cadherin enables cells to break loose from each other and is considered as a crucial step in EMT7,8. Noncanonical repressor DEAD-box RNA helicases (DDXs), such as DDX3X and DDX5, are associated with the loss of E-cadherin in cancers, but DDX3X prefers to bind distal region of the E-cadherin promoter[15,16]. At present, it is not well understood how these factors couple to transcriptional repressors, and whether there are communications among these complexes on the E-cadherin promoter in cancer
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