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Twist is a key transcription factor for Epithelial-mesenchymal transition (EMT), which is a cellular de-differentiation program that promotes invasion and metastasis, confers tumor cells with cancer stem cell (CSC)-like characteristics and increases therapeutic resistance. However, the mechanisms that facilitate the functions of Twist remain unclear. Here we report that Twist overexpression increased expression of PAR1, an upstream regulator of the Hippo pathway; PAR1 promotes invasion, migration and CSC-like properties in breast cancer by activating the transcriptional co-activator TAZ. Our study indicates that Hippo pathway inhibition is required for the increased migratory and invasiveness ability of breast cancer cells in Twist-mediated EMT.

BRD4 assembles transcriptional machinery at gene super-enhancer regions and governs the expression of genes that are critical for cancer progression. However, it remains unclear whether BRD4-mediated gene transcription is required for tumor cells to develop drug resistance. Our data show that prolonged treatment of luminal breast cancer cells with AKT inhibitors induces FOXO3a dephosphorylation, nuclear translocation, and disrupts its association with SirT6, eventually leading to FOXO3a acetylation as well as BRD4 recognition. Acetylated FOXO3a recognizes the BD2 domain of BRD4, recruits the BRD4/RNAPII complex to the CDK6 gene promoter, and induces its transcription. Pharmacological inhibition of either BRD4/FOXO3a association or CDK6 significantly overcomes the resistance of luminal breast cancer cells to AKT inhibitors in vitro and in vivo. Our study reports the involvement of BRD4/FOXO3a/CDK6 axis in AKTi resistance and provides potential therapeutic strategies for treating resistant breast cancer. The molecular mechanism underlying the resistance of AKT inhibitors in breast cancer is still elusive. Here, the authors demonstrate that BRD4/FOXO3a axis upregulates CDK6 promoter activity to promote resistance to AKT inhibition in breast cancer cells and that blocking the action of CDK6 re-sensitizes resistant cancer cells to growth inhibition.

Vascularization is an important factor that affects diabetic wound healing. There is increasing evidence that myeloid cell lineages play a role in neovascularization. In this study, the efficiency of Gr‐1+CD11b+ myeloid cells to home to the site of injury and enhance diabetic wound healing by neoangiogenesis after intravenous administration was investigated. Gr‐1+CD11b+ myeloid cells were injected into tail vein after establishment of dorsal window chamber, hindlimb ischaemia and ear‐punch injury in diabetic or non‐diabetic mice. The Gr‐1+CD11b+ myeloid cells efficiently homed to the site of injury after intravenous administration and increased neoangiogenesis. The chemokine receptor type 4 (CXCR4) is robustly expressed by Gr‐1+CD11b+ myeloid cells. Inhibition of CXCR4 decreases the homing ability of Gr‐1+CD11b+ myeloid cells to the site of injury, which indicates that the CXCR4/SDF‐1 axis plays an important role in the homing of Gr‐1+CD11b+ myeloid cells to the site of injury. In addition, Gr‐1+CD11b+ myeloid cells were found to improve blood flow recovery of ischaemic limb and enhance wound healing in diabetic mice by neoangiogenesis after intravenous administration. Taken together, the results of this study suggest that Gr‐1+CD11b+ myeloid cells may serve as a potential cell therapy for diabetic wound healing.

Vascularization is an important factor that affects diabetic wound healing. There is increasing evidence that myeloid cell lineages play a role in neovascularization. In this study, the efficiency of Gr‐1+ CD 11b+ myeloid cells to home to the site of injury and enhance diabetic wound healing by neoangiogenesis after intravenous administration was investigated. Gr‐1+ CD 11b+ myeloid cells were injected into tail vein after establishment of dorsal window chamber, hindlimb ischaemia and ear‐punch injury in diabetic or non‐diabetic mice. The Gr‐1+ CD 11b+ myeloid cells efficiently homed to the site of injury after intravenous administration and increased neoangiogenesis. The chemokine receptor type 4 ( CXCR 4) is robustly expressed by Gr‐1+ CD 11b+ myeloid cells. Inhibition of CXCR 4 decreases the homing ability of Gr‐1+ CD 11b+ myeloid cells to the site of injury, which indicates that the CXCR 4/ SDF ‐1 axis plays an important role in the homing of Gr‐1+ CD 11b+ myeloid cells to the site of injury. In addition, Gr‐1+ CD 11b+ myeloid cells were found to improve blood flow recovery of ischaemic limb and enhance wound healing in diabetic mice by neoangiogenesis after intravenous administration. Taken together, the results of this study suggest that Gr‐1+ CD 11b+ myeloid cells may serve as a potential cell therapy for diabetic wound healing.