Induced Lysosomal Targeted Degradation of the Oncogenic RNA-Binding Protein HuR Complex

Abstract The RNA-binding protein HuR (ELAVL1) is frequently overexpressed and aberrantly localized in cancer cells, where it enhances the stability and translation of numerous transcripts involved in proliferation, survival, invasion, and resistance to therapy. HuR contains multiple RNA-recognition motifs and regulates a broad network of oncogenic mRNAs. Consequently, inhibition of a single RNA-binding pocket is often insufficient to fully suppress its oncogenic activity, as HuR may retain RNA-binding and regulatory functions through its remaining domains. Complete elimination of HuR and its associated ribonucleoprotein complexes may provide a more effective therapeutic strategy than conventional occupancy-based inhibition. Here, we present an induced-proximity approach that redirects HuR-containing complexes toward lysosomal degradation. We developed bifunctional molecules designed to simultaneously bind HuR and engage p62, a selective autophagy receptor that promotes cargo sequestration and subsequent lysosomal clearance. The lead compound induced efficient HuR degradation in breast cancer cells through a lysosome-dependent mechanism. This degradation was accompanied by reduced expression of major HuR-regulated oncogenic targets and a marked decrease in breast cancer cell proliferation and viability. These findings establish p62-mediated lysosomal degradation of HuR complexes as a promising anticancer strategy and provide a broader framework for targeting oncogenic RNA-binding protein networks. More broadly, this work provides a foundation for a next-generation therapeutic platform aimed at targeting previously difficult-to-drug oncogenic RNA-protein networks.