Targeting ribosomal DNA transcription and nucleolar chromatin in cancer — ASN Events
  1. Schedule
  2. Session 4A: Regulation of gene expression 1
  3. Targeting ribosomal DNA transcription and nucleolar chromatin in cancer

Targeting ribosomal DNA transcription and nucleolar chromatin in cancer (#21)

Jeannine Diesch 1 , Megan J Bywater 1 , Donald P Cameron 1 2 , Natalie Brajanovski 1 , Jinbae Son 1 2 , Nadine Hein 3 , Richard B Pearson 1 2 4 , Grant A McArthur 1 2 5 6 7 , Austen RD Ganley 8 , Justin M O'Sullivan 9 , Ross D Hannan 1 2 3 4 10 11 , Gretchen Poortinga 1 2 5
  1. Peter MacCallum Cancer Centre, East Melbourne, VIC, Australia
  2. Sir Peter MacCallum Department of Oncology, University of Melbourne, Parkville, VIC, Australia
  3. John Curtain School of Medical Research, Australian National University, Canberra, ACT, Australia
  4. Department of Biochemistry and Molecular Biology, University of Melbourne, Parkville, VIC, Australia
  5. Department of Medicine, St. Vincent's Hospital, Fitzroy, VIC, Australia
  6. Department of Pathology, University of Melbourne, Parkville, VIC, Australia
  7. Division of Cancer Medicine, Peter MacCallum Cancer Centre, East Melbourne, VIC, Australia
  8. Department of Biological Sciences, University of Auckland, Auckland, New Zealand
  9. Liggins Institute, University of Auckland, Auckland, New Zealand
  10. Department of Biochemistry and Molecular Biology, Monash University, Clayton, VIC, Australia
  11. School of Biomedical Sciences, The University of Queensland, St. Lucia, QLD, Australia

Increased RNA polymerase I (Pol I) transcription of the 200 ribosomal RNA genes (rDNA) is consistently observed in human cancers and our development of the novel Pol I transcription inhibitor CX-5461 to treat solid and hematopoietic cancers while sparing normal cells, has led to CX-5461 entering clinical trials1. Notably, ~50% of rRNA genes are typically transcriptionally silent2. Our studies demonstrate that silent rDNA repeats are reactivated as cells transition to malignancy. Critically we find that this reactivation (rDNA class-switching) and subsequent nucleolar reorganization is essential for tumour cell survival, independent of rDNA transcription. Using the Eμ-Myc mouse model of spontaneous lymphoma we utilized RNA-seq, ChIP-seq and 4C-seq to demonstrate that rDNA class-switching may drive changes in global genome organization, resulting in transcriptome changes that underlie tumour cell dependence. This talk will present evidence for rDNA-chromatin's role in cancer progression and offer novel insights into the spatial and transcriptional dynamics of the rDNA-associated genome during malignant transformation. Further, we make the connection between the highly specialised transcriptional context of rDNA, how that influences mechanisms of resistance to Pol I transcription inhibition and the hypothesis that targeting epigenetic and transcriptional regulators in combination with CX-5461 will render cancer cells highly sensitive to checkpoint activation.

  1. 1. Bywater et al., Cancer Cell, 2012
  2. 2. McStay B. and Grummt I., Annu Rev Cell Dev Biol, 2008
#LorneGenome