Cells frequently encounter conditions that can damage them or even lead to cell death. To keep functioning, they must rapidly adjust which genes are active so they can protect themselves. Cancer cells face even more intense challenges because the environment around a tumor is often harsh and unstable. Despite this, they manage to flourish by activating gene programs that support larger tumor growth and the ability to spread to new areas of the body.
Until now, it was unclear how cancer cells transform stressful surroundings into an advantage. Researchers at Rockefeller suspected the answer would come from understanding how the cell's transcription machinery detects these conditions and shifts its activity. Their work has now identified a molecular switch inside breast cancer cells that redirects gene activity toward stress tolerance and tumor expansion.
The study, reported in Nature Chemical Biology, points to a possible new therapeutic target.
"This previously unknown transcription-level mechanism helps the cancer cells survive stressful conditions, so targeting it could disrupt a key survival mechanism that some cancers rely on," says first author Ran Lin, a research associate from the Laboratory of Biochemistry and Molecular Biology at The Rockefeller University. "It's another example of how basic research can open promising therapeutic avenues."
"We found that this molecular switch is mediated by a generic transcription complex normally required for all protein-coding genes," says Robert Roeder, head of the lab. "But what was most unexpected is that its individual subunits can be repurposed for several physiological functions -- including a function that allows cancer cells to survive and grow in high-stress environments."
Key Transcription Players and the Role of MED1
RNA polymerase II, also called Pol II, is the enzyme responsible for transcribing protein-coding genes in eukaryotic cells. Roeder originally discovered Pol II, and it often works together with the Mediator complex, a large coactivator made up of 30 subunits, to initiate the first steps of transcription. Additional adjustments to the resulting RNA can occur through post-transcriptional modifications, which further influence gene expression.
One important Mediator subunit is MED1. It is required for Pol II transcription in many cell types, including estrogen receptor-positive breast cancer (ER+ BC), which is one of the most common breast cancer categories.
Roeder's lab previously showed that interactions between estrogen receptors and MED1 strongly activate gene expression in ER+ BC. In some cases, this interaction can even reduce the effectiveness of cancer drugs. These earlier findings led Lin to question whether MED1 might also support cancer cell survival when the cells are under stress.
Investigating MED1 and Acetylation
Lin began by examining whether MED1 undergoes acetylation. Acetylation involves the addition of an acetyl group to a protein, and this chemical modification can alter how proteins function. Scientists are increasingly recognizing the impact of acetylation on tumor growth, cancer spread, and treatment resistance.
Once Lin confirmed that MED1 is acetylated, he investigated how this modification affects its activity during stressful conditions. The researchers exposed cells to several types of stress, including hypoxia (lack of oxygen), oxidative stress, and heat stress.
Stress Response Through Deacetylation
The team discovered that during stress, a protein known as SIRT1 removes acetyl groups from MED1. This process, referred to as "deacetylation," allows MED1 to partner more effectively with Pol II, boosting the potential for activating protective genes.
To further test this mechanism, the researchers engineered a version of MED1 missing six specific acetylation sites, which made it incapable of being acetylated. They then placed this modified protein into ER+ breast cancer cells where the natural MED1 had been removed using CRISPR.
The results were clear: whether MED1 was deacetylated due to stressful conditions or because it simply could not be acetylated, the outcome was the same. Breast cancer cells containing deacetylated MED1 produced tumors that grew more quickly and showed higher resistance to stress.
A Regulatory Switch Linked to Tumor Growth
"Our work reveals that the acetylation and deacetylation of MED1 act as a regulatory switch that helps cancer cells reprogram transcription in response to stress, supporting both survival and growth," Lin says. "In cancer -- particularly in ER+ breast cancer -- this pathway may be co-opted or intensified to support abnormal growth and survival. We hope these insights will inform future drug development, especially for breast cancers and possibly other malignancies that rely on stress-induced gene reprogramming."
"This MED1 regulatory pathway appears to be part of a wider paradigm in which acetylation regulates transcription factors," Roeder adds. "Our earlier work on p53 helped establish that principle. Continuing to probe these basic mechanisms is what allows us to identify pathways that may eventually be leveraged for therapeutic purposes."
