Metastatic progression and therapeutic resistance require cancer cells to rapidly adapt to cellular stress through dynamic post-transcriptional regulation of gene expression. RNA-binding proteins (RBPs) are central regulators of these adaptive responses; however, many remain poorly characterised. We identified ZCCHC24, an uncharacterised RBP, as a mesenchymal-specific regulator of triple-negative breast cancer progression.
ZCCHC24 expression is induced during epithelial-to-mesenchymal transition (EMT) upon loss of the epithelial miR-200 family and is selectively upregulated in mesenchymal breast cancer cells. CLIP-sequencing revealed hundreds of ZCCHC24 RNA targets, with binding sites enriched adjacent to Pumilio recognition motifs, suggesting a cooperative mode of target recognition between these two RBPs.
Mechanistically, we demonstrate that ZCCHC24 functions as a regulator of selective mRNA translation rather than transcription. Loss of ZCCHC24 reduces protein expression of multiple pro-metastatic targets, including integrins, without corresponding changes in mRNA abundance, indicating translational control of cancer-promoting transcripts. Furthermore, we identify ZCCHC24 as a stress granule-associated RBP that redistributes to cytoplasmic RNA granules following oxidative stress. ZCCHC24 exhibits extensive co-localisation with the stress granule markers G3BP1, TIAR and FMRP, and its depletion disrupts stress granule organisation, resulting in altered TIAR- and FMRP-positive granule formation. These findings support a role for ZCCHC24 in coordinating stress-responsive RNA metabolism during tumour adaptation.
Functionally, we demonstrated ZCCHC24 to be essential for maintaining the mesenchymal phenotype and drives breast cancer cell migration, invasion and metastatic colonisation. Genetic depletion of ZCCHC24 profoundly reduced metastasis to lung tissue in vivo, establishing ZCCHC24 as a key regulator of tumour dissemination. Collectively, our findings identify ZCCHC24 as a previously unrecognised RBP that promotes metastatic progression. Targeting ZCCHC24-mediated translational control may represent a novel therapeutic strategy for aggressive breast cancers.