In a groundbreaking study published in the “Cancer Research” journal (DOI: 10.1158/0008-5472.CAN-18-2070), researchers have unveiled how collagen prolyl hydroxylation (CPH) serves as an epigenetic switch that plays a pivotal role in regulating cellular state transitions in both pluripotent stem cells and cancer cells. The study, led by Dr. Cristina D’Aniello and a team of scientists from the Stem Cell Fate Laboratory at the Institute of Genetics and Biophysics ‘A. Buzzati-Traverso’ (CNR) in Naples, Italy, along with collaborators from IFOM, the FIRC Institute of Molecular Oncology, and IRBM, Naples, Italy, has significant implications for understanding the mechanisms behind cancer metastasis and stem cell differentiation.
Collagen prolyl hydroxylation is the most common posttranslational modification in humans and is catalyzed by an enzyme known as prolyl 4-hydroxylase (P4H). This biochemical process, which also depends on the presence of vitamin C (VitC), plays a crucial role in the proper folding and stability of collagen proteins that form the extracellular matrix of tissues. The new findings demonstrate that CPH not only affects the physical properties of collagen but also has a profound impact on the cell’s epigenetic landscape and its capacity to transition between different states.
The study found that increased levels of CPH lead to a boost in global DNA and histone methylation, resulting in epigenetic modifications that favor cell state transition (CST), including the mesenchymal transition seen in metastatic cancer cells and the dynamic state changes in pluripotent stem cells. By either genetically knocking down the enzyme P4H subunit alpha-2 (P4HA2) or using pharmacological approaches to disrupt CPH, researchers were able to reverse these epigenetic changes and impede CST.
The team’s research further suggests that the mechanism by which CPH governs these changes is tied to its consumption of VitC. Given that vitamin C is a cofactor for DNA and histone demethylases, a reduction in VitC availability due to increased CPH activity results in a decrease in demethylation, thereby promoting DNA and histone methylation and consequent changes in gene expression. This, in turn, drives cells towards a mesenchymal and more invasive phenotype, which is a hallmark of metastatic cancer cells.
Interestingly, the study also revealed that repurposed drugs, such as budesonide—a medication commonly used to treat asthma—can successfully target CPH-mediated metabolic disturbances. The researchers demonstrated that budesonide blocks the metastatic spread of breast cancer cells in animal models, offering a potential new therapeutic approach for combating cancer metastasis.
The findings of this research carry significant weight in the scientific community, elucidating a novel epigenetic mechanism that contributes to cancer progression and the manipulation of stem cell states. For the broader medical community and patients, this study represents a promising step towards developing new therapeutic strategies for cancer treatment and regenerative medicine.
References
1. D’Aniello C. et al. (2019). Collagen Prolyl Hydroxylation-Dependent Metabolic Perturbation Governs Epigenetic Remodeling and Mesenchymal Transition in Pluripotent and Cancer Cells. Cancer Research, 79(13):3235-3250. DOI: 10.1158/0008-5472.CAN-18-2070.
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Keywords
1. Collagen prolyl hydroxylation
2. Cancer metastasis
3. Epigenetic remodeling
4. Stem cell plasticity
5. Prolyl 4-hydroxylase inhibitors