Loss of ZNRF3/RNF43 unleashes EGFR in cancer

Cancer research · Colorectal cancer · EGFR

Loss of the E3 ubiquitin ligases ZNRF3 and RNF43 leads to increased EGFR expression and signaling, promoting cancer cell growth and tumorigenesis.

ZNRF3 and RNF43 are closely related transmembrane E3 ubiquitin ligases with significant roles in development and cancer. Conventionally, their biological functions have been associated with regulating WNT signaling receptor ubiquitination and degradation. However, our proteogenomic studies have revealed EGFR as the protein most negatively correlated with ZNRF3/RNF43 mRNA levels in multiple human cancers. Through biochemical investigations, we demonstrate that ZNRF3/RNF43 interact with EGFR via their extracellular domains, leading to EGFR ubiquitination and subsequent degradation facilitated by the E3 ligase RING domain. Overexpression of ZNRF3 reduces EGFR levels and suppresses cancer cell growth in vitro and in vivo, whereas knockout of ZNRF3/RNF43 stimulates cell growth and tumorigenesis through upregulated EGFR signaling. Together, these data suggest ZNRF3 and RNF43 as novel E3 ubiquitin ligases of EGFR and establish the inactivation of ZNRF3/RNF43 as a driver of increased EGFR signaling, ultimately promoting cancer progression. This discovery establishes a connection between two fundamental signaling pathways, EGFR and WNT, at the level of cytoplasmic membrane receptors, uncovering a novel mechanism underlying the frequent co‑activation of EGFR and WNT signaling in development and cancer.

The findings reveal a novel mechanism by which the loss of ZNRF3 and RNF43 licenses EGFR hyper‑activation, a well‑known driver of many solid tumors. Elucidating this crosstalk between WNT and EGFR signaling pathways provides new therapeutic avenues for cancers that concurrently harbor mutations or amplifications in either pathway.

Evidence level: Klinikai vizsgálat. Formális klinikai vizsgálati eredmény.

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