Human Neuralized is a novel tumour suppressor targeting Wnt/β‐catenin signalling in colon cancer.

While there is growing evidence that many epigenetically silenced genes in cancer are tumour suppressor candidates, their significance in cancer biology remains unclear. Here, we identify human Neuralized (NEURL), which acts as a novel tumour suppressor targeting oncogenic Wnt/β‐catenin signalling in human cancers. The expression of NEURL is epigenetically regulated and markedly suppressed in human colorectal cancer. We, therefore, considered NEURL to be a bona fide tumour suppressor in colorectal cancer and demonstrate that this tumour suppressive function depends on NEURL‐mediated oncogenic β‐catenin degradation. We find that NEURL acts as an E3 ubiquitin ligase, interacting directly with oncogenic β‐catenin, and reducing its cytoplasmic levels in a GSK3β‐ and β‐TrCP‐independent manner, indicating that NEURL‐β‐catenin interactions can lead to a disruption of the canonical Wnt/β‐catenin pathway. This study suggests that NEURL is a therapeutic target against human cancers and that it acts by regulating oncogenic Wnt/β‐catenin signalling. Synopsis: Neuralized (NEURL) is a novel tumour suppressor targeting the oncogenic Wnt/β‐catenin pathway in colorectal cancer by promoting β‐catenin degradation independent of GSK3β and β‐TrCP. NEURL hypermethylation is associated with poor outcomes in patients with colon cancer.NEURL acts as a tumour suppressor in colon cancer by inhibiting cell proliferation and interrupting tumorigenesis.NEURL targets β‐catenin as an E3 ubiquitin ligase impairing oncogenic WNT signalling in colorectal cancer. [ABSTRACT FROM AUTHOR]