A groundbreaking study conducted by researchers at the Spanish National Cancer Research Centre (CNIO) has unveiled a previously unrecognized molecular mechanism that instigates colorectal cancer, providing vital new insights into its early onset and progression. This discovery centers on the degradation of the tumor suppressor protein p53, a protein conventionally revered as the “guardian of the genome” for its pivotal role in controlling cell division and preventing malignancies. Contrary to earlier understandings that tumorigenesis is primarily triggered by genetic mutations leading to loss of p53 function, this research reveals that the active degradation of p53 protein itself initiates colorectal tumor formation in its earliest stages.
Colorectal cancer stands as the third most diagnosed malignancy globally, with a substantial proportion of cases linked to environmental and lifestyle contributors, including dietary habits, sedentariness, obesity, smoking, and excessive alcohol intake. Most colorectal malignancies arise from adenomatous polyps—premalignant lesions that, if undetected or untreated, can evolve into aggressive tumors. The CNIO’s study elucidates how perturbations at the molecular level during these initial polyp stages can decisively influence whether a malignancy develops and progresses.
The research team, spearheaded by Dr. Nabil Djouder, Head of the Growth Factors, Nutrients and Cancer Group at CNIO, deployed sophisticated animal models to dissect the molecular evolution of colon cancer. Through these models, the investigators detected an early and significant degradation of p53 protein coinciding with the formation of adenomas. Traditionally, p53 was known to suppress tumors by inducing cell cycle arrest or apoptosis upon DNA damage or oncogenic stress; however, this study confirms that its quantitative loss through degradation—even before genetic loss or mutation—facilitates unchecked cellular proliferation and genomic instability, thereby catalyzing tumor initiation.
A remarkable aspect of the findings is the identification of a new regulatory axis involving the protein URI, which appears to govern p53 stability. While URI has been previously implicated in cancers such as hepatocellular carcinoma, its contribution to colorectal cancer was previously uncharted territory. The data reveal that increased URI expression induces targeted p53 protein degradation, thus abrogating its tumor-suppressive actions. This mechanistic insight opens avenues to potentially intercept the carcinogenic process by modulating URI activity before the tumor advances.
Additionally, the study illuminates the involvement of the oncogene MYC in this regulatory pathway. MYC is a well-known driver of cellular proliferation and tumorigenesis through transcriptional activation of multiple downstream targets. Here, MYC is shown to activate URI expression, which in turn promotes p53 degradation, intertwining oncogenic signaling pathways and protein stability control to facilitate early colon tumor development. This molecular crosstalk offers a nuanced perspective on how oncogene activation translates into functional protein perturbations during cancer onset.
Expanding the scope of their research, the CNIO team demonstrated that experimentally inhibiting URI or restoring p53 levels in mouse models prevented adenomas from progressing into malignant tumors. This not only prolonged survival in these animal models but also underscored the therapeutic potential of targeting the URI-p53 axis. The pursuit of URI inhibitors emerges as a promising preventative and therapeutic strategy to halt colorectal cancer at its inception, offering hope for improved patient prognosis and diminished disease burden.
The implications of this work extend beyond fundamental biology, offering a robust framework for understanding how environmental and lifestyle factors may interface with molecular mechanisms to elevate colorectal cancer risk. Prior studies from Dr. Djouder’s group have hinted at URI’s responsiveness to environmental variables such as diet, suggesting that lifestyle modifications may modulate URI expression and consequently influence p53 stability and colorectal cancer risk.
Importantly, this study distinguishes the early stage p53 protein degradation from the later-stage genetic loss of the TP53 gene, which occurs in advanced colorectal cancers and correlates with aggressive phenotypes and metastasis. This biphasic model—early protein degradation followed by genetic loss—provides a more comprehensive picture of tumor evolution and highlights distinct windows for intervention.
Verification of these findings was bolstered by analysis of human colorectal tissue samples, ranging from adenomas to advanced carcinomas, obtained through extensive collaborations and biobanking efforts. Complementary bioinformatics analyses reinforced the molecular associations uncovered in animal models, cementing the relevance of this mechanism in human disease.
This paradigm-shifting research underscores the critical importance of protein homeostasis in cancer initiation, suggesting that molecular degradation pathways can be as influential as genetic mutations in driving oncogenesis. By pioneering studies on p53 degradation and its regulation by URI and MYC, CNIO researchers have charted a new course toward innovative preventative and therapeutic solutions for colorectal cancer, a disease of profound global impact.
As biomedical science advances, the demand for therapies addressing early-stage molecular disruptions gains urgency. The development of URI-specific inhibitors not only holds promise in colorectal cancer but may also benefit a spectrum of URI-associated malignancies. CNIO’s ongoing research endeavors aim to translate these foundational discoveries into viable clinical interventions, potentially revolutionizing cancer care paradigms.
In summary, this study reveals a novel initiating mechanism of colorectal cancer whereby URI-driven degradation of the tumor suppressor p53 sets the stage for tumorigenesis. The intricate interplay between oncogene MYC, URI protein expression, and p53 degradation forms a complex regulatory network that favors neoplastic transformation. Targeting this axis offers newfound opportunities for early intervention, prevention, and treatment of colorectal cancer, paving the way for enhanced patient outcomes and reduced disease burden worldwide.
Subject of Research: Animals
Article Title: p53 protein degradation redefines the initiation mechanisms and drives transitional mutations in colorectal cancer
News Publication Date: 26-Apr-2025
Web References:
https://www.nature.com/articles/s41467-025-59282-4
References:
Djouder, N., Herranz-Montoya, I., et al. (2025). p53 protein degradation redefines the initiation mechanisms and drives transitional mutations in colorectal cancer. Nature Communications. DOI: 10.1038/s41467-025-59282-4
Image Credits: Sladjana Zagorac / CNIO
Keywords: Colorectal cancer, Protein expression, Mutation, Molecular genetics, Preventive medicine, Translational research
