1. Academic Validation
  2. Transcriptional Regulation of Protein Synthesis by Mediator Kinase Represents a Therapeutic Vulnerability in MYC-driven Medulloblastoma

Transcriptional Regulation of Protein Synthesis by Mediator Kinase Represents a Therapeutic Vulnerability in MYC-driven Medulloblastoma

  • Res Sq. 2024 Nov 1:rs.3.rs-5329081. doi: 10.21203/rs.3.rs-5329081/v1.
Dong Wang 1 2 Caitlin Ritz 1 Angela Pierce 1 2 Bethany Veo 1 2 Yuhuan Luo 3 Breauna Brunt 1 Nathan Dahl 1 2 Ammu Suresh 1 Natalie Serkova 4 Sujatha Venkataraman 1 2 Etienne Danis 5 Kamil Kuś 6 Milena Mazan 6 Tomasz Rzymski 6 Rajeev Vibhakar 1 2 7
Affiliations

Affiliations

  • 1 Department of Pediatrics, University of Colorado Anschutz Medical Campus; Aurora, CO, USA.
  • 2 Morgan Adams Foundation Pediatric Brain Tumor Research Program, Children's Hospital Colorado; Aurora, CO, USA.
  • 3 Department of Surgery, University of Colorado Anschutz Medical Campus; Aurora, CO, USA.
  • 4 Department of Radiology, University of Colorado Anschutz Medical Campus; Aurora, CO, USA.
  • 5 Biostatistics and Bioinformatics Shared Resource, University of Colorado Cancer Center, Aurora; CO, USA.
  • 6 RVYU Therapeutics; Krakow, Poland.
  • 7 Department of Neurosurgery, University of Colorado Anschutz Medical Campus; Aurora, CO, USA.
Abstract

MYC-driven medulloblastoma (MB) is a highly aggressive Cancer type with poor prognosis and limited treatment options. Through CRISPR-Cas9 screening of MB cell lines, we identified the Mediator-associated kinase CDK8 as a critical regulator of MYC-driven MB. Loss of CDK8 substantially reduces MYC expression, induces pronounced transcriptional changes, suppresses monosome assembly, and decreases ribosome biogenesis and protein synthesis, consequently inhibiting MB growth. Mechanistically, CDK8 regulates the occupancy of RNA polymerase II at specific chromatin loci, facilitating an epigenetic alteration that promotes the transcriptional regulation of ribosomal genes. Targeting CDK8 effectively diminishes the stem-like neoplastic cells characterized by hyperactive ribosome biogenesis. Furthermore, we demonstrated that the combined inhibition of CDK8 and mTOR synergizes to optimize therapeutic outcomes in vivo and in vivo. Overall, our findings establish a connection between CDK8-mediated transcriptional regulation and mRNA translation, suggesting a promising new therapeutic approach that targets the protein synthesis for MYC-driven MB.

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