Investigating Inhibition of MYCN in the Treatment of Wilms' Tumour

Abstract

Wilms’ Tumour, or Nephroblastoma, is the most common paediatric renal cancer and though survival rates have increased over the last decade the anaplastic subtype display rates as low as 18%. The poor prognosis anaplastic Wilms’ Tumour subtype has displayed a greater level of MYCN expression, a known oncoprotein, and while genetic alteration of MYCN has been reported, no biological functional studies have been conducted. Here I have shown that MYCN depletion via small interfering RNA results in growth suppression whereas PRMT5 depletion leads to both growth suppression and apoptosis. This PRMT5 depletion resulted in a total reduction of MYCN protein and transcript levels. I also demonstrate that BRD4 potentially shares a positive feedback loop with MYCN and is regulated by PRMT5. Here I have also shown for the first time through co-Immunoprecipitation that MYCN directly interacts with PRMT5 in WiT49 cells which are of an anaplastic subtype. Together this potentiates a synthetic lethal relationship between MYCN and PRMT5 which could be exploited in the targeted treatment of MYCN overexpressing Wilms’ Tumour cases. Using a current PRMT5 inhibitor, GSK591, the alterations to MYCN protein and transcript levels were synonymous to the functional studies conducted. In sum, this project has identified PRMT5 as an excellent novel target in the treatment of MYCN overexpressing Wilms’ Tumour.

Date of Award	23 Jan 2020
Original language	English
Awarding Institution	The University of Bristol
Supervisor	Karim T A Malik (Supervisor) & Keith W Brown (Supervisor)