Poster Presentation 35th Lorne Cancer Conference 2023

The role of UBF in malignant transformation (#172)

Vrinda Johri 1 , Thejaani Udumanne 1 , Anran Lin 1 , Mark Le Deux 2 , Ross Hannan 1 3 , Nadine Hein 1 , Rita Ferreira 1
  1. Australian National University, Canberra, ACT, Australia
  2. Department of Neurology and Anatomy & Neurobiology, University of Tennessee Health Science Center, Memphis, Tennessee, United States of America
  3. Division of Cancer Research, Peter MacCallum Cancer Centre, Melbourne, Victoria, Australia

A prognostic marker for cancer cells is the increase in nucleolar number or size. This reflects in an increase in ribosome biogenesis (Ribi), the process responsible for ribosome production, necessary for cancer cells to maintain high levels of cell growth and proliferation. The rate limiting step of RiBi is the transcription of ribosomal DNA (rDNA) by RNA polymerase I (Pol I). Consequently, an increase in ribosomal RNA (rRNA) is observed in cancer cells.

The Upstream Binding Factor (UBF) plays a major role in initiating Pol I-mediated rDNA transcription. Increased binding of UBF to rDNA has been shown to occur during spontaneous malignant transformation in the Eµ-Myc lymphoma mouse model.

Recently, a novel variant of UBF (UBFE210K)  was identified in paediatric neurodegenerative disorders. UbfE210K mouse embryonic fibroblasts show a reduction in rDNA transcription due to  reduced binding of Pol I to rDNA.  Therefore, we hypothesise that UBFE210K may inhibit/delay cancer progression by preventing the increase in Pol I-mediated rDNA transcription.

To investigate the effect of UBFE210K on malignancy progression we crossed UbfE210K mice with Eµ-Myc mice. Eu-Myc mice  express the Myc oncogene under the control of the IgH enhancer (Eμ). These animals spontaneously develop lymphoma characterized by an increase in Pre B-cells. Preliminary data show that Eµ-Myc UbfE210K/WT mice still develop lymphoma similarly to Eµ-Myc UbfWT/WT suggesting that the presence of the wild-type UBF, albeit at a reduced level, is still sufficient to allow malignant transformation. UbfE210K mutation shows no effect on  the pre-B cells in the absence of Eµ-Myc.

Through this research, we hope to unravel how UBFE210K influences Pol I transcription and cancer progression and validate the potential UBF has as a target for novel cancer therapies.