USP7 inactivation suppresses APC-mutant intestinal hyperproliferation and tumor development

Abstract

Truncating mutation of the tumor suppressor gene adenomatous polyposis coli (APC) is the hallmark of colorectal cancer (CRC), resulting in constitutive WNT activation. Despite decades of research, targeting WNT signaling in cancer remains challenging due to its essential role in normal stem cell maintenance. We have previously shown that the deubiquitinating enzyme USP7 is a tumor-specific WNT activator in APC-truncated cells by deubiquitinating and stabilizing {beta}-catenin, but its role in gut tumorigenesis is unknown. Here we show in vivo that deletion of Usp7 in Apc-truncated mice inhibits crypt hyperproliferation and intestinal tumor development. Importantly, intestine-specific Usp7 mutation does not yield any phenotype in wildtype animals, indicating that its loss is well tolerated. Unexpectedly, prolonged deletion of Usp7 in Apc+/- intestine induces varying degrees of colitis. Treatment with a USP7 inhibitor suppresses growth of patient-derived cancer organoids in vitro and of xenografts carrying APC truncations. We propose that USP7 inhibition may be efficacious for tumor-specific therapy of sporadic APC-mutated CRC, while patients with germline APC mutations should not receive such treatment. HighlightsO_LIUsp7 deletion in Apc-truncated mice reduces intestinal tumor development. C_LIO_LIIntestine-specific Usp7 mutation mutation has no phenotype in wildtype animals. C_LIO_LITreatment with Usp7 inhibitor suppresses growth of patient-derived cancer organoids carrying Apc truncations in vitro and of xenografts. C_LI