Poster Presentation 28th Lorne Cancer Conference 2016

Dysregulation of Pol I transcription in ovarian cancer (#255)

Jinbae Son 1 2 , Karen E Sheppard 1 2 3 , Jessica Ahern 2 , Katherine M Hannan 2 4 , Gretchen Poortinga 2 5 , Austen R.D. Ganley 6 , Richard B Pearson 1 2 3 7 , Elaine Sanij 2 8 , Ross D Hannan 2 4 7 9
  1. Sir Peter MacCallum Department of Oncology, University of Melbourne, Melbourne, VIC, Australia
  2. Research division, Peter MacCallum Cancer Centre, Melbourne, VIC, Australia
  3. Department of Biochemistry and Molecular Biology, University of Melbourne, Parkville, VIC, Australia
  4. Department of Cancer Biology and Therapeutics, The John Curtin School of Medical Research, Acton, ACT, Australia
  5. Department of Medicine, St Vincent's hospital, University of Melbourne, Fitzroy, VIC, Australia
  6. Institue of Natural and Mathematical Sciences, Massey University, Albany, Auckland, New Zealand
  7. Department of Biochemistry and Molecular Biology, Monash University, Clayton, VIC, Australia
  8. Department of Pathology, University of Melbourne, Parkville, VIC, Australia
  9. School of Biomedical Sciences, University of Queensland, Brisbane, QLD, Australia

Transcription of the 300 copies of ribosomal RNA (rRNA) genes (rDNA) by RNA polymerase I (Pol I) is the first critical step in ribosome biogenesis, and accounts for 35~60% of all cellular transcription. Dysregulation of rDNA transcription is a consistent feature of human cancers. Although rDNA transcription is growth limiting, only a subset of rRNA genes is transcribed at any given time(1, 2).

Our studies utilising the Em-Myc transgenic mouse model of B-cell lymphoma demonstrate a dramatic increase in rDNA transcription rates as B-cells progress towards malignancy. Our laboratory has also demonstrated that inhibition of Pol I transcription by CX-5461 can selectively kill B-lymphoma cells in vivo, while sparing wild type B-cells (3). However, the mechanisms underlying sensitivity to CX-5461 are still unclear.

We have undertaken a systematic approach across a panel of ovarian cancer (OVCA) cell lines to examine their sensitivity to CX-5461. Our preliminary data show that OVCA cell lines display similar sensitivities to Pol I transcription inhibition however they exhibit differential cellular responses, involving either an immediate or a delayed cell cycle arrest. Furthermore, our studies suggest that increased active rDNA chromatin and not rDNA transcription rate per se is associated with a prompt growth inhibitory response to CX-5461 treatment of OVCA cells.

Further, the highly repetitive nature of rRNA genes renders the rDNA loci one of the most fragile sites in the genome and its structural alterations have been reported in over 50% of solid human cancers (4).

Our preliminary data utilizing genome-editing tools to delete rDNA repeats suggests that cancer cells with reduced rDNA content display genomic instability and defects in cell proliferation despite minimal changes in rDNA transcription rate. Thus, rDNA plays an important role in promoting genome stability independent of rDNA transcription. Taken together, our data suggest a role for rDNA instability in cancer development.

  1. 1. Sanij E, Poortinga G, Sharkey K, Hung S, Holloway TP, Quin J, et al. UBF levels determine the number of active ribosomal RNA genes in mammals. The Journal of cell biology. 2008;183(7):1259-74.
  2. 2. Sanij E, Diesch J, Lesmana A, Poortinga G, Hein N, Lidgerwood G, et al. A novel role for the Pol I transcription factor UBTF in maintaining genome stability through the regulation of highly transcribed Pol II genes. Genome research. 2015;25(2):201-12.
  3. 3. Bywater MJ, Poortinga G, Sanij E, Hein N, Peck A, Cullinane C, et al. Inhibition of RNA polymerase I as a therapeutic strategy to promote cancer-specific activation of p53. Cancer cell. 2012;22(1):51-65.
  4. 4. Stults D, Killen M, Williamson E, Hourigan J, Vargas H, Arnold S, et al. Human rRNA gene clusters are recombinational hotspots in cancer. Cancer research. 2009;69:9096 - 104.