Project description:We isolated an efficient tetracycline degrading strain Sphingobacterium sp. WM1. To investigate gene expression patterns during tetracycline degradation by strain WM1, we conducted a comparative transcriptomic analysis using cultures of strain WM1 with and without tetracycline addition. The RNA-Seq data revealed that 90.44-96.56% of the reads mapped to the genome of Sphingobacterium sp. WM1 across all samples. Differentially expressed genes (DEGs) analysis (|log2FC| >2; p < 0.01) showed that 693 genes were significantly up-regulated and 592 genes were significantly down-regulated.
Project description:Cyclin-dependent kinase 9 (CDK9) stimulates oncogenic transcriptional pathways in cancer. Here, we evaluate the activity of an orally bioavailable CDK9 inhibitor, CDKI-73, in prostate cancer, a disease characterized by aberrant activity of multiple transcriptional regulators. CDKI-73 caused inhibition of proliferation and cell death in diverse in vitro models of androgen receptor (AR)-driven and AR-independent models of castration-resistant prostate cancer (CRPC). The activity of CDKI-73 was validated in more clinically-relevant systems, including xenografts, patient-derived tumor explants and aggressive patient-derived CRPC organoids. Mechanistically, CDKI-73 inhibited CDK9-mediated phosphorylation of serine 2 on RNA polymerase II and serine 81 on AR. This resulted in reduced levels of anti-apoptotic factors and suppression of signaling pathways regulated by AR, MYC and BRD4, key drivers of dysregulated transcription in prostate cancer. CDKI-73 synergized with the BRD4 inhibitor AZD5153 in cell lines and organoid models of aggressive AR-driven and AR-independent disease. Collectively, our work provides new insights into CDK9’s oncogenic activity and reveals CDKI-73 as a promising therapeutic agent for prostate cancer, particularly aggressive, therapy-resistant subtypes.
