Elucidating novel mechanisms for growth control and cancer progression: linking RAS and PI3K pathways with MYC transcription via FUBP1 — ASN Events
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  2. Poster Session 2
  3. Elucidating novel mechanisms for growth control and cancer progression: linking RAS and PI3K pathways with MYC transcription via FUBP1

Elucidating novel mechanisms for growth control and cancer progression: linking RAS and PI3K pathways with MYC transcription via FUBP1 (#207)

Olga Zaytseva 1 2 , Jue Er Amanda Lee 1 , Naomi C Mitchell 1 2 , Linna Guo 1 2 , Arjun Chahal 1 2 , Rodney Luwor 3 , David L Levens 4 , Ross D Hannan 2 5 , Leonie M Quinn 1 2
  1. University of Melbourne, Parkville, VIC, Australia
  2. The John Curtin School of Medical Research, ANU, Canberra, ACT, Australia
  3. Royal Melbourne Hospital, Parkville, VIC, Australia
  4. National Institute of Health, Bethesda, Maryland, USA
  5. Peter MacCallum Cancer Centre, Melbourne, VIC, Australia

The transcription factor MYC is upregulated in 70% of cancers. Most MYC-driven cancer arises from increased expression, but the networks controlling MYC transcription in malignancy remain poorly understood. In particular, understanding the links between signaling pathways and downstream transcriptional effectors could provide avenues for overcoming resistance to therapeutics targeting upstream components, which is frequently displayed by cancer cells.

The single stranded DNA binding protein FUBP1 regulates transcription of MYC, and dysregulation of FUBP1 has been linked with a wide variety of cancers. In particular, TCGA data (>500 patients) ranks FUBP1 in the top 8% of overexpressed genes in glioblastoma (invasive glioma or GBM), the most common and deadliest brain malignancy in adults. Glioblastomas frequently (50-60%) manifest ectopic activity
of the upstream receptor tyrosine kinases (or RTKs) that feed into the highly oncogenic RAS and PI3K pathways.

We have recently shown that regulation of MYC by FUBP1 is conserved between Drosophila and mammals (Guo, Zaysteva et al, 2016). As RAS and PI3K pathways are highly conserved between mammals and invertebrates, we used Drosophila models to demonstrate that glial overproliferation driven by EGFR/RAS/PI3K requires activation of MYC transcription via FUBP1. We also observe high expression of FUBP1 in glioblastoma stem cells (GSCs) from patients and, as MYC is essential for GSC renewal and glioblastoma progression, we predict RTK/RAS/PI3K drives tumourigenesis, at least in part, via FUBP1-dependent MYC transcription.

L. Guo, O. Zaytseva, Z. Nie, N.C. Mitchell, J.E.A. Lee, T. Ware, L. Parsons, R. Luwor, G. Poortinga, R.D. Hannan, D.L. Levens, and L.M. Quinn, "Defining the essential function of FBP/KSRP proteins: Drosophila Psi interacts with the mediator complex to modulate MYC transcription and tissue growth", Nucleic Acids Res. gkw461, 2016.

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