Poster Presentation 46th Lorne Genome Conference 2025

A novel RNA binding protein (ZCCHC24) promotes EMT through widespread regulation of post-transcriptional gene expression (#141)

Shruti Deshpande 1 , Daniel P Neumann 1 , Caroline A Chambers 1 , Kate Dredge 1 , Rachael Lumb 1 , Millicent GA Bennett 1 , Andrew G Bert 1 , John Toubia 1 , Cameron P Bracken 1 , Katherine A Pillman 1 , Greg J Goodall 1 , Philip A Gregory 1
  1. University of South Australia, Adelaide, SA, Australia

Epithelial to mesenchymal transition (EMT) plays a significant role in facilitating cancer cell invasion, tumor metastasis, and therapy resistance. In a screen for novel regulators of EMT, we uncovered an uncharacterized CCHC type Zinc finger protein (ZCCHC24) that is highly induced in mesenchymal cells and directly repressed by the epithelial-specific miR-200 family in epithelial cells. Unlike well-known EMT-driving transcription factors, we identify ZCCHC24 as a cytoplasmic RNA binding protein (RBP) that orchestrates widespread post-transcriptional changes in gene expression.  Knockout of ZCCHC24 caused breast cancer cells to lose mesenchymal features including a reduction in invasive capacity, while overexpression of ZCCHC24 caused the opposite phenotypes. 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 RBP Pumilio (PUM) in many cases, directly interacted with PUM, and knockout of PUM negatively affected ZCCHC24 function. We propose that the ZCCHC24-PUM complex is an important regulator of post-transcriptional gene expression changes driving cancer-associated EMT.