Poster Presentation 28th Lorne Cancer Conference 2016

RNAi screens identify mutant p53 regulators (#259)

Kah Hin Tan 1 2 , Reshma Vijayakumaran 1 2 , Franco Caramia 1 2 , Piyush Madhamshettiwar 3 , Daniel W Thomas 3 , Jennii Luu 3 , David S. H. Liu 2 4 , Sue Haupt 1 2 , Kaylene J Simpson 2 3 , Ygal Haupt 1 2
  1. Tumour Suppression Laboratory, Peter MacCallum Cancer Centre, Melbourne
  2. Sir Peter MacCallum Department of Oncology, University of Melbourne, East Melbourne, Victoria, Melbourne
  3. Victorian Centre For Functional Genomics, Peter MacCallum Cancer Centre, Melbourne
  4. Cancer Biology and Surgical Oncology Laboratory, Peter MacCallum Cancer Centre, Melbourne
TP53 is mutated in more than 50% of all human cancers, and the resulting mutant proteins often accumulate and acquire pro-oncogenic properties, “Gain-of-Function” (GOF), to drive tumourigenesis1 . Recent evidence demonstrated ­— targeting mutant p53 stabilization and tumour dependence on mutant p53 GOF as a promising approach for cancer treatment2 . In this study, we aim to identify novel regulators of mutant p53, decipher mechanism(s) underlying mutant p53 stabilization, and define their potential as therapeutic targets for cancer therapy.We performed genome-wide RNAi screens (protein-coding genes siRNA, microRNAs, long non-coding RNAs) on cancer cell-lines bearing endogenous mutant p53, and analyzed the mutant protein level and subcellular localization using high-content analysis. Candidate hits were triaged on secondary screens, and validated on multiple cancer cell-lines (tertiary screens). These candidate hits will be evaluated in vitro, for their effects on mutant p53 GOF and their roles underlying mutant p53 stabilization. Finally, the identified regulators — proteins, microRNAs and lncRNAs — will be analyzed-bioinformatically to better map the mutant p53 regulatory network.Our study has identified potential novel mutant p53 regulators (proteins, microRNAs and lncRNAs) to be further studied.
  1. Oren, M. and V. Rotter, Mutant p53 gain-of-function in cancer. Cold Spring Harb Perspect Biol, 2010. 2(2): p. a001107.
  2. Alexandrova, E.M., et al., Improving survival by exploiting tumour dependence on stabilized mutant p53 for treatment. Nature, 2015. 523(7560): p. 352-6.