ABSTRACT
Mediator kinases (CDK8/19) are transcriptional regulators broadly implicated in cancer. Despite their central role in fine-tuning gene-expression programs, we find complete loss of CDK8/19 is tolerated in colorectal cancer (CRC) cells. Using orthogonal functional genomic and pharmacological screens, we identify BET protein inhibition as a distinct vulnerability in CDK8/19-depleted cells. Combined CDK8/19 and BET inhibition led to synergistic growth retardation in human and mouse models of CRC. Strikingly, depletion of CDK8/19 in these cells led to global repression of RNA polymerase II (Pol II) promoter occupancy and transcription. Concurrently, loss of Mediator kinase led to a profound increase in MED12 and BRD4 co-occupancy at enhancer elements and increased dependence on BET proteins for the transcriptional output of cell-essential genes. In total, this work demonstrates a synthetic lethal interaction between Mediator kinase and BET proteins and exposes a therapeutic vulnerability that can be targeted using combination therapies.
Subject(s)
Cell Cycle Proteins/metabolism , Cell Proliferation , Colorectal Neoplasms/enzymology , Cyclin-Dependent Kinase 8/metabolism , Cyclin-Dependent Kinases/metabolism , Mediator Complex/metabolism , Nuclear Proteins/metabolism , Transcription Factors/metabolism , Adult , Aged , Aged, 80 and over , Animals , Antineoplastic Combined Chemotherapy Protocols/therapeutic use , Binding Sites , Cell Cycle Proteins/antagonists & inhibitors , Cell Cycle Proteins/genetics , Cell Proliferation/drug effects , Colorectal Neoplasms/drug therapy , Colorectal Neoplasms/genetics , Cyclin-Dependent Kinase 8/genetics , Cyclin-Dependent Kinases/genetics , Enhancer Elements, Genetic , Female , Gene Expression Regulation, Neoplastic , HCT116 Cells , Humans , Male , Mediator Complex/antagonists & inhibitors , Mediator Complex/genetics , Mice, Inbred BALB C , Mice, Knockout , Mice, Nude , Nerve Tissue Proteins/antagonists & inhibitors , Nerve Tissue Proteins/genetics , Nerve Tissue Proteins/metabolism , Nuclear Proteins/antagonists & inhibitors , Nuclear Proteins/genetics , Protein Kinase Inhibitors/pharmacology , Receptors, Cell Surface/antagonists & inhibitors , Receptors, Cell Surface/genetics , Receptors, Cell Surface/metabolism , Signal Transduction , Transcription Factors/antagonists & inhibitors , Transcription Factors/genetics , Transcription, Genetic , Tumor Burden , Xenograft Model Antitumor AssaysABSTRACT
Vaginal evisceration is a rare condition where abdominal contents herniate through a vaginal wall defect. The estimated incidence is 0.032-1.2% after hysterectomy, trachelectomy or upper vaginectomy. We present a 78-year-old lady who developed vaginal evisceration 2 years after radical cystectomy and hysterectomy for bladder cancer. It is rare surgical emergency that requires prompt recognition and damage control with bowel reduction and packing. We discuss the initial management and surgical options for definitive repair.
