Decoding PRDM16-DT: A Hidden Protein Regulating Colorectal Cancer Metastasis and Chemoresistance

Colorectal cancer is one of the most common and deadliest cancers worldwide. The biggest challenge with this disease is not just its ability to grow, but its tendency to spread and resist treatment. Once colorectal cancer reaches an advanced stage and spreads to other parts of the body, survival rates drop significantly. While treatments like surgery and chemotherapy have helped many patients, they are not always enough. Cancer cells are incredibly adaptive, finding ways to survive even the most aggressive treatments. This ability to resist chemotherapy leads to treatment failure, relapse, and, ultimately, a poor prognosis for many patients. Scientists have been trying to understand why this happens and how to stop it. Tumors that spread are often the same ones that resist chemotherapy, and tumors that develop resistance tend to spread more easily. Traditional research has focused on well-known cancer genes, but this has not led to major breakthroughs in overcoming resistance. In recent years, however, researchers have started looking at a different aspect of cancer biology—long non-coding RNAs, or lncRNAs. For a long time, these molecules were thought to be unimportant, simply genetic “junk.” But newer studies have shown that lncRNAs actually play a major role in controlling how genes work, and some even produce small proteins that had been completely overlooked. A new research published in Theranostics Journal and conducted by Dr. Hui-Fang Hu, Lei Han, Jia-Ying Fu, Xuan He, Ji-Feng Tan, Qing-Ping Chen, Jing-Ru Han, and Professor Qing-Yu He from the Jinan University, decided to investigate whether any of these hidden proteins could be influencing colorectal cancer progression. Their study, published in Theranostics, focused on LINC00982, a lncRNA previously linked to cancer suppression. Using advanced gene-editing technology and tumor models, they discovered that LINC00982 produces a small protein called PRDM16-DT, which plays an important role in stopping cancer from spreading and resisting chemotherapy. They found that PRDM16-DT helps regulate RNA splicing, a process that determines how genes are read and turned into proteins. Mistakes in splicing can fuel cancer progression and resistance to treatment. The team then searched for a way to increase PRDM16-DT levels in drug-resistant cancer cells. After screening a collection of natural compounds, they found that cimicifugoside H-1, a plant-derived molecule, could boost PRDM16-DT by blocking FOXP3, a protein that suppresses it. This discovery could lead to new treatments that make chemotherapy more effective while also slowing down cancer’s ability to spread.

The research team set out to find new ways to stop colorectal cancer from spreading and resisting treatment. They used CRISPR/Cas9 screening, a powerful genetic tool, to scan aggressive cancer cells for key regulators that might be influencing these processes. Their search led them to PRDM16-DT, a protein that was present at much lower levels in metastatic cancer cells. This immediately caught their attention. If metastatic cells had less of it, could boosting its levels slow cancer down? To find out, they engineered cancer cells to produce more PRDM16-DT and saw a dramatic drop in their ability to move and invade surrounding tissues. On the other hand, when they reduced PRDM16-DT, the cells became far more aggressive, confirming its role as a suppressor of cancer spread. Curious about how PRDM16-DT worked, the authors focused on RNA splicing, a process that determines how genes are read and turned into proteins. They discovered that PRDM16-DT interacts with HNRNPA2B1, a protein involved in splicing, and affects a gene called CHEK2, which helps repair damaged DNA. PRDM16-DT blocked HNRNPA2B1 from binding to a specific part of CHEK2, which pushed cells to produce a longer, tumor-suppressing version of the protein known as L-CHEK2. Without PRDM16-DT, the shorter version, S-CHEK2, became more common, making cancer cells more invasive and harder to treat.  To confirm these findings in living organisms, they injected cancer cells with different levels of PRDM16-DT into mice. The results were striking. Mice injected with PRDM16-DT-rich cancer cells developed fewer and smaller tumors in their lungs. Those given cells with little to no PRDM16-DT had widespread metastasis. Tumors with high PRDM16-DT also had more E-cadherin, a protein that keeps cells tightly packed together and prevents them from spreading. PRDM16-DT-induced E-cadherin secretion inhibited activation of fibroblasts in a paracrine manner. They then examined human clinical tumor samples and found that PRDM16-DT was much lower in metastatic cancers. Patients with low PRDM16-DT levels had worse survival rates. Further analysis revealed that PRDM16-DT was being suppressed by FOXP3, a transcription factor that normally regulates immune function. They confirmed that FOXP3 physically binds to the PRDM16-DT gene and silences it, especially in advanced cancers. Looking for a way to reverse this suppression, they screened natural compounds and found one that could block FOXP3—cimicifugoside H-1. Treating cancer cells with this compound restored PRDM16-DT levels, reduced invasiveness, and made drug-resistant cells sensitive to chemotherapy again. In mice, combining cimicifugoside H-1 with chemotherapy dramatically reduced metastasis and improved survival, offering a promising path for future treatment strategies.

In conclusion, the researchers at Jinan University made an important discovery that could change how colorectal cancer is diagnosed and treated. They found that PRDM16-DT is not just another protein, but a key player in stopping cancer from spreading. What makes this finding so significant is its potential to help doctors predict which patients are at higher risk for aggressive cancer. Their study showed that people with lower levels of PRDM16-DT had worse survival rates, suggesting that this protein could be used as a biomarker. If further studies confirm this, oncologists could measure PRDM16-DT levels to determine which patients are more likely to have their cancer spread or become resistant to chemotherapy. This kind of insight could allow doctors to tailor treatments to each patient’s needs, giving them the best possible chance of survival while avoiding unnecessary treatments. But PRDM16-DT is not just a useful marker—it is also a potential treatment target. The research showed that this protein plays a crucial role in keeping cancer cells from spreading by helping the body produce a protective version of CHEK2, PRDM16-DT also strengthens the bonds between cells, making it harder for cancer to break free and invade other tissues. This highlights something that is often overlooked in cancer research—alternative splicing, the process of creating different versions of proteins from the same gene, can have a major impact on cancer progression. Instead of simply blocking cancer-causing genes, future treatments might work by influencing how genes are spliced, pushing cancer cells toward a less aggressive state. Perhaps the most exciting part of this study is the discovery of cimicifugoside H-1, a natural compound that can increase PRDM16-DT levels by blocking FOXP3, a protein that shuts it down. Unlike traditional chemotherapy, which often comes with severe side effects, this compound works by restoring the body’s natural ability to fight cancer. It offers a completely different approach—one that is less about killing cancer cells directly and more about helping the body regain control over them. Moreover, these findings could also lead to more personalized cancer treatments. Since PRDM16-DT levels are different from patient to patient, therapies that target this pathway could be designed for those who need it most. This could make treatments more effective while reducing unnecessary interventions, giving patients a better chance at long-term survival and improved quality of life.