Pseudouridine, a modified building block of RNA, is gaining recognition for its unexpected involvement in cancer. This alteration to RNA molecules is emerging as a significant area of research, highlighting how even slight molecular changes can have far-reaching effects on cellular processes, including those that go awry in cancer. Understanding its role offers new avenues for exploring cancer’s complexities.
Understanding Pseudouridine
Pseudouridine is a common modification found across various types of RNA, including transfer RNA (tRNA), ribosomal RNA (rRNA), and small nuclear RNA (snRNA). It differs from standard uridine because its ribose sugar is attached to the fifth carbon atom of the uracil base, rather than the usual nitrogen atom. This unique carbon-carbon bond provides pseudouridine with greater rotational freedom and conformational flexibility compared to uridine.
The formation of pseudouridine is catalyzed by specific enzymes called pseudouridine synthases (PUS). These enzymes convert a uridine already incorporated into an RNA chain into pseudouridine through an isomerization reaction. This modification stabilizes RNA structures, influences RNA-protein interactions, and contributes to the accurate decoding of genetic information during protein synthesis.
Pseudouridine’s Contribution to Cancer Progression
Altered levels or specific modifications of pseudouridine can contribute to several hallmarks of cancer, influencing uncontrolled cell growth, survival, and spread. Pseudouridylation can significantly alter RNA structure and stability, impacting processes like pre-mRNA splicing, RNA stability, and translation. This can lead to the dysregulation of gene expression, which is often observed in cancer cells.
Pseudouridine can promote uncontrolled cell growth. Increased expression of pseudouridine synthases like DKC1 has been observed in various cancers, including colorectal cancer, and is associated with poor prognosis. DKC1 influences ribosomal RNA pseudouridylation and ribosome biogenesis, which can lead to the synthesis of proteins that promote cancerous transformation.
Pseudouridine also plays a role in cell survival and evasion of programmed cell death (apoptosis). Modified RNA structures, stabilized by pseudouridine, can affect translation fidelity, potentially leading to the production of abnormal proteins that help cancer cells survive or resist cell death signals. Dysregulation of PUS enzymes can impair RNA function, contributing to tumor development.
Pseudouridine’s influence extends to cancer cell migration and invasion. Elevated DKC1 expression has been linked to increased angiogenesis and metastasis in colorectal cancer by activating HIF-1α transcription, a pathway involved in tumor growth and spread.
Pseudouridine may contribute to drug resistance. Changes in RNA modifications, including pseudouridylation, can alter the expression of genes involved in drug metabolism or efflux, making cancer cells less susceptible to chemotherapy or other treatments.
Pseudouridine has been implicated in various cancer types, including digestive system cancers like liver and colorectal cancer, as well as non-digestive system cancers such as breast cancer, non-small cell lung cancer, and prostate cancer. The precise mechanisms differ based on the specific PUS enzyme involved and the type of RNA modified, but the overarching theme is that altered pseudouridylation supports the aggressive characteristics of cancer cells.
Pseudouridine as a Biomarker for Cancer
The presence of altered pseudouridine levels in biological samples presents a promising avenue for its use as a diagnostic or prognostic indicator in cancer. Pseudouridine can be detected in human blood, urine, and tissue samples using various methods. Studies have shown that patients with malignant tumors, including thyroid, lung, breast, and liver cancer, often exhibit elevated levels of modified nucleosides, particularly pseudouridine, in their blood and urine.
This characteristic elevation suggests its potential for early detection. For example, serum pseudouridine levels are significantly higher in patients with hepatocellular carcinoma compared to healthy individuals, indicating its value as a diagnostic marker. In colorectal cancer, elevated pseudouridine modifications have been found in oncogenes within tumor tissues, correlating with established clinical biomarkers.
Beyond early detection, pseudouridine could also serve in prognosis, predicting disease progression or patient outcomes. The “Psi Score,” a measure of pseudouridine modification patterns, has been shown to vary across tumor stages in colorectal cancer, with higher scores in advanced stages, suggesting its involvement in tumor progression. Monitoring pseudouridine levels could also help track the effectiveness of therapies, offering a way to assess treatment response non-invasively. While its potential is significant, further research is needed to fully validate pseudouridine as a standalone biomarker and integrate it into routine clinical practice.
Exploring Pseudouridine as a Therapeutic Target
The emerging understanding of pseudouridine’s role in cancer progression has led to exploration of targeting pseudouridine or its modifying enzymes as a strategy for cancer treatment. One primary approach involves inhibiting pseudouridine synthases (PUS), the enzymes responsible for creating pseudouridine. Since overexpression of PUS enzymes is common in cancer cells and often predicts a poor prognosis, blocking their activity could hinder tumor growth.
Studies indicate that inhibiting PUS enzymes can arrest cancer cell proliferation and enhance programmed cell death, or apoptosis. This suggests that drugs designed to specifically target these enzymes could offer new anti-cancer therapies. For example, targeting DKC1, a specific pseudouridine synthase, with small-molecule inhibitors is being investigated as a potential therapy for oral squamous cell carcinoma.
Other strategies could involve modulating overall pseudouridine levels to normalize the abnormal modifications found in cancer cells. While specific drugs directly targeting pseudouridine pathways are largely in experimental stages, the concept highlights a unique molecular vulnerability in cancer cells that could be exploited.