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Method for Measuring the Activity of Deubiquitinating Enzymes in Cell Lines and Tissue Samples
Published on: May 10, 2015
The deubiquitinase USP28 controls intestinal homeostasis and promotes colorectal cancer
Abstract:
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 USP28 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 USP28 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.
Insights
The deubiquitinase USP28 stabilizes c-MYC, promoting colorectal cancer growth. Inhibiting USP28 reduces intestinal tumors, decreases proliferation, and extends lifespan, offering a potential new cancer therapy.
Area of Science:
- Oncology
- Molecular Biology
- Genetics
Background:
- Colorectal cancer is a leading global malignancy.
- The transcription factor c-MYC is frequently misregulated in colorectal tumors but difficult to target directly.
- The deubiquitinase USP28 stabilizes oncogenic factors, including c-MYC, but its role in intestinal tumorigenesis is unclear.
Purpose of the Study:
- To investigate the role of USP28 in intestinal homeostasis and colorectal cancer development.
- To determine if USP28 contributes to the stabilization of c-MYC, c-JUN, and NOTCH1 in the intestine.
- To evaluate the therapeutic potential of targeting USP28 in colorectal cancer models.
Main Methods:
- Utilized murine genetic models to study the function of Usp28.
- Assessed the impact of Usp28 deletion on intestinal proliferation, differentiation, and tumor development.
- Analyzed the expression of Usp28 in murine and human intestinal cancers and its relationship with c-MYC.
Main Results:
- Usp28 deficiency in mice led to reduced intestinal proliferation and impaired secretory cell differentiation without apparent adverse phenotypes.
- Deletion of Usp28 in a colorectal cancer model resulted in fewer tumors, smaller tumor size, and significantly increased lifespan.
- Usp28 was identified as a c-MYC target gene highly expressed in intestinal cancers, forming a positive feedback loop with c-MYC.
- Usp28 deficiency promoted tumor cell differentiation and decreased proliferation, mirroring its effects in normal intestinal homeostasis.
Conclusions:
- USP28 plays a critical role in maintaining intestinal homeostasis and promoting colorectal cancer progression by stabilizing oncogenic factors like c-MYC.
- USP28 inhibition demonstrates therapeutic potential by reducing tumor growth, promoting differentiation, and extending survival in colorectal cancer.
- Targeting the enzymatic activity of USP28 represents a promising strategy for colorectal cancer therapy.
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