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 β-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.

中文翻译：

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USP7 失活抑制 APC 突变体肠道过度增殖和肿瘤发展

肿瘤抑制基因腺瘤性息肉病 (APC) 的截断突变是结直肠癌 (CRC) 的标志，导致组成型 WNT 激活。尽管进行了数十年的研究，但由于其在正常干细胞维持中的重要作用，靶向癌症中的 WNT 信号传导仍然具有挑战性。我们之前已经表明，去泛素化酶 USP7 通过去泛素化和稳定 β-连环蛋白是 APC 截短细胞中的肿瘤特异性 WNT 激活剂，但其在肠道肿瘤发生中的作用尚不清楚。在这里，我们在体内显示 Apc 截短小鼠中 Usp7 的缺失抑制了隐窝过度增殖和肠道肿瘤的发展。重要的是，肠道特异性 Usp7 突变不会在野生型动物中产生任何表型，这表明它的损失是可以耐受的。不料，Apc+/- 肠中 Usp7 的长时间缺失会导致不同程度的结肠炎。用 USP7 抑制剂治疗可抑制患者衍生的癌症类器官在体外的生长和携带 APC 截断的异种移植物的生长。我们建议 USP7 抑制可能对散发性 APC 突变的 CRC 的肿瘤特异性治疗有效，而具有种系 APC 突变的患者不应接受这种治疗。