Stabilisation of β-Catenin-WNT signalling by USP10 in APC-truncated colorectal cancer drives cancer stemness and enables super-competitor signalling

Abstract The contribution of deubiquitylating enzymes to β-Catenin stabilisation in intestinal stem cells and colorectal cancer (CRC) is poorly understood. Here, we report the deubiquitylase USP10 as an APC-truncation- specific enhancer of β-Catenin stability, potentiating WNT signalling and cancer stem cells and CRC. Mechanistically, interaction and in vitro binding studies, together with computational modelling, revealed that USP10 binding to β-Catenin is mediated via the unstructured N-terminus of USP10 and requires the absence of full-length APC. Reduction of USP10 induces the expression of differentiation genes and opposes the APC-truncated phenotype in an intestinal hyperplasia model. Notably, loss of USP10 in CRISPR engineered intestinal organoids opposed the super competitor-signalling and reduced tumorigenic properties of APC-mutated CRC. Taken together, our findings reveal USP10s role in CRC cell identity, stemness and tumour growth by stabilising β-Catenin, leading to aberrant WNT signalling, and implicate USP10 as a cancer specific therapeutic vulnerability in Apc truncated CRC.