Lactylation-driven SENP1 promotes colon cancer malignant progression by mediating FRS2 deSUMOylation modification

Colon cancer is a relentless disease that thrives on the body's own energy systems. To understand how it grows so aggressively, scientists look at the microscopic instructions inside our cells. These instructions are written in DNA, but they are also managed by a complex layer of chemical tags that tell genes when to switch on or off. One such tag, called lactylation, acts like a switch that turns on genes when the cell is burning sugar for energy. Another process, known as SUMOylation, works like a molecular anchor, attaching small proteins to other proteins to keep them stable and functional. When these chemical systems go wrong, cancer cells can hijack them to grow faster, spread to other parts of the body, and consume energy at a dangerous rate. Researchers have long suspected that these chemical tags are central to the disease, but the specific chain of events that links sugar metabolism to cancer growth has remained unclear.

A team of scientists at the Affiliated Changshu Hospital of Nantong University has now traced a direct line between these chemical processes and the aggressive behavior of colon cancer. They discovered that a specific protein, which acts as a master regulator, is driven by the lactylation tag to keep cancer cells alive and thriving. This protein, called SENP1, functions by removing a different type of tag from another protein, FRS2. By stripping away this tag, SENP1 prevents FRS2 from breaking down, allowing it to accumulate and drive the cancer forward. The study reveals that this entire mechanism is fueled by the high levels of lactic acid produced by cancer cells as they feast on sugar.

The researchers began by looking at tissue samples from patients with colon cancer and comparing them to healthy tissue. They found that the levels of SENP1 were significantly higher in the cancer samples. To see what this protein actually does, they silenced it in cancer cells grown in the lab. Without SENP1, the cancer cells stopped growing, lost their ability to spread, and could no longer consume sugar as efficiently. This suggested that SENP1 is a critical engine for the disease. The team then asked what SENP1 was controlling. Using computer analysis of gene data, they identified a protein called FRS2 as a likely target. Further experiments confirmed that when SENP1 was present, FRS2 levels were high; when SENP1 was removed, FRS2 levels dropped.

The connection between these two proteins relies on a chemical process called deSUMOylation. In healthy cells, proteins are often tagged with SUMO molecules, which can mark them for destruction or alter their function. SENP1 acts as a pair of molecular scissors that cuts these SUMO tags off. The researchers found that SENP1 removes the SUMO tag from FRS2, which stabilizes the protein and keeps it active. When they prevented SENP1 from doing this job, FRS2 became unstable and disappeared, causing the cancer cells to lose their malignant edge. To prove this was the key mechanism, they forced the cancer cells to produce extra FRS2 even without SENP1. This restored the cancer cells' ability to grow and spread, confirming that FRS2 is the primary tool SENP1 uses to drive the disease.

The story does not end with SENP1 and FRS2. The researchers wanted to know what turns SENP1 on in the first place. They suspected the answer lay in the high levels of lactic acid found in tumors. Cancer cells are known to produce vast amounts of lactic acid as a byproduct of their rapid sugar consumption. This acid can attach to histones, which are spools that hold DNA, creating a lactylation tag. The team found that the specific tag on a histone called H3K18 was much higher in cancer tissues than in healthy ones. They discovered that this H3K18 lactylation tag sits directly on the DNA segment that controls the SENP1 gene. When the tag is present, it acts as a powerful switch, turning on the production of SENP1.

To verify this, the scientists reduced the amount of lactic acid produced by the cancer cells. This lowered the H3K18 lactylation tag, which in turn reduced the amount of SENP1 being made. The cancer cells then behaved more like normal cells, growing slower and spreading less. However, when they added lactic acid back into the mix, the tag reappeared, SENP1 levels rose, and the cancer cells returned to their aggressive state. This confirmed a complete cycle: the cancer cells produce lactic acid, which creates a chemical tag on their DNA, which turns on the SENP1 gene, which stabilizes FRS2, which drives the cancer to grow and spread.

This research provides a clear picture of how colon cancer cells rewire their own biology to survive and thrive. It shows that the metabolic waste product of the tumor, lactic acid, is not just a byproduct but a signal that actively reprograms the cell's genetic machinery. By linking the sugar-burning process directly to the genes that control cell growth, the study identifies a specific chain of events that could be targeted for treatment. The findings suggest that interrupting this loop—whether by blocking the production of lactic acid, preventing the lactylation tag from forming, or stopping SENP1 from stabilizing FRS2—could potentially slow down or stop the progression of the disease. While these results are currently based on cell cultures and mouse models, they offer a promising new direction for understanding the molecular roots of colon cancer.