BET bromodomain inhibitors (BETi), such as JQ1, have been demonstrated to effectively kill multiple types of cancer cells. However, the underlying mechanisms for BETi resistance remain largely unknown. Our evidences show that JQ1 treatment evicts BRD4 from the FOXD3-localized MIR548D1 gene promoter, leading to repression of miR-548d-3p. The loss of miRNA restores JunD expression and subsequent JunD-dependent transcription of RPS6KA2 gene. ERK1/2/5 kinases phosphorylate RSK3 (RPS6KA2), resulting in the enrichment of activated RSK3 and blockade of JQ1 killing effect. Dual inhibition of MEKs/ERKs or single EGFR inhibition are able to mimic the effect of JunD/RSK3-knockdown to reverse BETi resistance. Collectively, our study indicates that loss of BRD4/FOXD3/miR-548d-3p axis enhances JunD/RSK3 signalling and determines BET inhibition resistance, which can be reversed by targeting EGFR-MEK1/2/5-ERK1/2/5 signalling.

PA28α/β activated immunoproteasome frequently participates in MHC class I antigen processing, however, whether it is involved in breast tumor progression remains largely unclear. Here, our evidences show that PA28α/β proteins are responsible for breast cancer cell migration, invasion, and metastasis. Knockdown of immunoproteasome core subunit β5i also robustly suppresses the tumor cell migration and invasion. Interestingly, silencing of PA28α/β and β5i up-regulates the protein expression of cyclin-dependent kinase 15 (CDK15). Our data further indicate that the loss of CDK15 is important for breast tumor cell invasion and metastasis. Taken together, this study implicates that targeting of PA28α/β represents a potential way for treatment of metastatic breast cancer.

ObjectiveThe purpose of this FE study was to analyze the biomechanical characteristics of different HS strategies used in the treatment of three-level CDDD (one-level CDA and two-level ACDF).MethodsWe validated the FE model of an intact cervical spine established by transferring the data, collected by 3D CT scan, to the FE software ABAQUS and comparing these data with the data from published studies. Then, the FE model of hybrid surgery was reconstructed to analyze the range of motion (ROM), facet joint force, and stress distribution on an ultrahigh molecular weight polyethylene (UHMWPE) core.ResultsThe current cervical FE model was able to measure the biomechanical changes in a follow-up hybrid surgery simulation. The total ROM of the cervical HS models was substantially decreased compared with the total ROM of the intact group, and the M2 (C3/4 ACDF, C4/5 CDA, and C5/6 ACDF) model had the closest total ROM to the intact group, but the facet joint force adjacent to the treatment levels showed very little difference among them. The stress distribution showed noticeable similarity: two flanks were observed in the center core, but the inlay of M2 was more vulnerable.ConclusionsThrough the comparison of ROM, the facet joint force after CDA, and the stress distribution of the prosthesis, we find that M2 model has a better theoretical outcome, especially in preserving the maximum total ROM.