Molecular Mechanisms Of Ring1b-mediated Chromatin Remodeling In Breast Cancer Metastasis

Breast cancer is the most common malignant tumor,and is the second leading cause of cancer death among women after lung cancer in the world.Metastasis is widely accepted as the major reason for mortality in patients with breast cancer.Epithelialmesenchymal transition(EMT)is a prerequisite for distant metastasis of tumor cells.Ring1 b is a core subunit of polycomb repressive complex 1(PRC1)and has monoubiquitylation E3 ligase activity specific for the lysine 119 of H2A(H2AK119ub)in eukaryotes.Ring1b-dependent PRC1 epigenetically modifies chromatin as transcriptional repressors and participates in the establishment and maintenance of cell fates.Accumulating evidence indicates that Ring1 b is essential in several high-risk cancers.However,the epigenetic mechanism of Ring1 b underlying EMT and metastasis of breast cancer is poorly understood.In this study,we showed that Ring1 b and its dependent epigenetic remodeling were activated in TGF-β-induced EMT model of breast epithelial cells.Increased Ring1b’s expression induced EMT in breast epithelial cells,and maintained metastasis of breast cancer cells in vitro and in vivo.We confirmed that Ring1 b could be selectively recruited by the members of ATP-dependent DEAD-box RNA helicases(DDXs)DDX3X/DDX5 and EMT transcription factors(EMT TFs)Snail1/Twist2,and showed the suppressive effect on the transcription of E-cadherin in multiple breast cell lines.Further study found that in normal epithelial cells or tumor epithelial cells,DDXsRing1 b complexes bound the proximal region of the E-cadherin promoter and induced cells at an early hybrid EMT state by moderately inhibiting E-cadherin.In mesenchymal cancer cells,EMT TFs-Ring1 b complexes preferred to bind distal region of the E-cadherin promoter,and led to E-cadherin silencing by cooperating with DDXsRing1 b complexes.Clinically,single and double factor analysis showed that high expression of Ring1 b with DDXs or EMT TFs predicted low levels of E-cadherin,metastatic behavior and poor prognosis.These findings provide the function of Ring1 b complexes in breast cancer and H2AK119ub-associated epigenetic regulation mechanism of E-cadherin expression in cancer metastasis.Ring1 b complexes may be potential therapeutic targets and biomarkers for diagnosis and prognosis in invasion breast cancer.