The deubiquitinase U5P28 controls intestinal homeostasis and promotes colorectal cancer
The deubiquitinase U5P28 controls intestinal homeostasis and promotes colorectal cancer
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DOI：
10.1172/jci73733
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发表时间：
2014-08-01
影响因子：
15.9
通讯作者：
Behrens, Axel
中科院分区：
文献类型：
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作者：
Diefenbacher, Markus E.;Popov, Nikita;Behrens, Axel
结直肠癌是全球第三大常见癌症。虽然转录因子c-MYC在大多数结直肠肿瘤中被错误调节，但难以直接靶向。去泛素化酶U 5 P28稳定致癌因子，包括c-MYC;然而，USP 28在肿瘤发生中的作用，特别是在肠道中，尚不清楚。在这里，使用鼠遗传模型，我们确定U 5 P28拮抗c-MYC的泛素依赖性降解，c-MYC是一种已知的USP 28底物，以及2种额外的致癌因子，c-JUN和NOTCH 1，在肠道中。缺乏Usp 28的小鼠没有明显的不良表型，但表现出肠道增殖减少和分泌谱系细胞分化受损。在结直肠癌的小鼠模型中，Usp 28缺失导致更少的肠道肿瘤，重要的是，在已建立的肿瘤中，Usp 28缺失减少了肿瘤大小并显着增加了寿命。此外，我们将Usp 28鉴定为在小鼠和人类肠癌中高度表达的c-MYC靶基因，这表明USP 28和c-MYC形成了一个正反馈环，可在肿瘤中维持高c-MYC蛋白水平。USP 28缺陷促进肿瘤细胞分化，同时伴有增殖减少，这表明USP 28在肠内稳态和结直肠癌模型中的作用相似。因此，抑制USP 28的酶活性可能是癌症治疗的潜在靶点。
Colorectal cancer is the third most common cancer worldwide. Although the transcription factor c-MYC is misregulated in the majority of colorectal tumors, it is difficult to target directly. The deubiquitinase U5P28 stabilizes oncogenic factors, including c-MYC; however, the contribution of USP28 in tumorigenesis, particularly in the intestine, is unknown. Here, using murine genetic models, we determined that U5P28 antagonizes the ubiquitin-dependent degradation of c-MYC, a known USP28 substrate, as well as 2 additional oncogenic factors, c-JUN and NOTCH1, in the intestine. Mice lacking Usp28 had no apparent adverse phenotypes, but exhibited reduced intestinal proliferation and impaired differentiation of secretory lineage cells. In a murine model of colorectal cancer, Usp28 deletion resulted in fewer intestinal tumors, and importantly, in established tumors, Usp28 deletion reduced tumor size and dramatically increased lifespan. Moreover, we identified Usp28 as a c-MYC target gene highly expressed in murine and human intestinal cancers, which indicates that USP28 and c-MYC form a positive feedback loop that maintains high c-MYC protein levels in tumors. Usp28 deficiency promoted tumor cell differentiation accompanied by decreased proliferation, which suggests that USP28 acts similarly in intestinal homeostasis and colorectal cancer models. Hence, inhibition of the enzymatic activity of USP28 may be a potential target for cancer therapy.