Poster Presentation 45th Lorne Genome Conference 2024

A novel rna binding protein (zcchc24) regulates cancer cell plasticity (#208)

Shruti Deshpande 1 , Daniel Neumann 1 , Caroline Phillips 1 , Kate Dredge 1 , Rachael Lumb 1 , Millicent Bennett 1 , Andrew Bert 1 , Katherine Pillman 1 , John Toubia 1 , Cameron Bracken 1 2 , Greg Goodall 1 2 , Philip Gregory 1 2
  1. Centre for Cancer Biology, University of South Australia, Adelaide, SA, Australia
  2. Faculty of Health and Medical Sciences, The University of Adelaide, Adelaide, SA, Australia

Cancer cell plasticity, which is commonly referred to as epithelial to mesenchymal transition (EMT), plays a significant role in facilitating cancer cell invasion, tumor metastasis, and therapy resistance. Understanding and treating cancers that have progressed to metastatic and therapy resistant states is a crucial challenge for human health. Our lab has previously shown that EMT is regulated by a feedback loop between the epithelial-specific miR-200 and the EMT transcription factor ZEB1. In a screen for novel regulators of EMT, we uncovered an uncharacterized CCHC type Zinc finger protein (ZCCHC24) that appears to regulate cellular plasticity. ZCCHC24 is repressed by miR-200 in epithelial cells, and it is highly induced in mesenchymal cells that lack miR-200. Unlike well-known EMT-driving transcription factors, we identified ZCCHC24 as a cytoplasmic RNA binding protein (RBP) that influences cancer cell plasticity, cell migration and invasion through post transcriptional modes of action. Using CLIP-seq we identified many RNA targets of ZCCHC24, but no specific binding motif was observed. However, ZCCHC24 bound near a consensus motif for the Pumilio RBP in many cases and interacted with Pumilio suggesting it may be required for ZCCHC24’s functions. Knockout of ZCCHC24 caused cancer cells to lose mesenchymal features including a reduction in invasive capacity, while overexpression of ZCCHC24 caused the opposite phenotypes. We propose that ZCCHC24 is a novel regulator of cancer-associated EMT and gaining an understanding of how it operates may lead to new treatment avenues for epithelial-derived cancers.