Scientists at The Rockefeller University have identified a crucial molecular mechanism that allows cancer cells, particularly those in breast cancer, to survive under stressful conditions. Their findings, published in Nature Chemical Biology, reveal how this mechanism can be targeted for potential new cancer treatments.
Cancer cells thrive in challenging environments, which often include low oxygen levels and other stressors. To adapt, they alter gene activity, enabling them to grow and spread aggressively. Researchers have long sought to understand how these cells convert stress into a survival advantage.
Through their investigation, the team discovered a molecular switch within breast cancer cells that redirects gene activity towards stress tolerance and tumor growth. First author Ran Lin, a research associate in the Laboratory of Biochemistry and Molecular Biology, emphasized the significance of this discovery: “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.”
Robert Roeder, head of the lab and a pioneer in the discovery of RNA polymerase II, explained that the switch is mediated by the Mediator complex, a coactivator essential for the transcription of protein-coding genes. The research highlights that individual subunits of this complex can be repurposed for various physiological functions, including aiding cancer cells in surviving high-stress environments.
Investigating the Role of MED1 in Cancer Survival
A critical component of this process is a Mediator subunit known as MED1. This protein is vital for the transcription process in various cell types, including estrogen receptor-positive breast cancer (ER+ BC), a prevalent form of breast cancer. Previous research showed that interactions between estrogen receptors and MED1 significantly activate gene expression in ER+ BC, sometimes even reducing the effectiveness of cancer treatments.
Lin’s curiosity about MED1’s role during stress prompted an examination of whether it undergoes acetylation, a modification that can influence protein function. The team confirmed that MED1 is indeed acetylated and proceeded to explore how this modification affects its activity in stressful conditions.
The researchers subjected breast cancer cells to multiple stressors, including hypoxia, oxidative stress, and heat stress. They discovered that during these conditions, a protein named SIRT1 removes acetyl groups from MED1. This process, known as deacetylation, enhances MED1’s ability to work with RNA polymerase II, thereby activating protective genes.
To further validate their findings, the team engineered a version of MED1 that lacked six specific acetylation sites, rendering it incapable of being acetylated. When introduced into ER+ breast cancer cells, the modified MED1 resulted in tumors that grew more rapidly and displayed greater resistance to stress.
Implications for Future Cancer Treatments
The results demonstrate that the acetylation and deacetylation of MED1 function as a regulatory switch that helps cancer cells adapt transcriptionally to stress, promoting both survival and growth. Lin noted, “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.”
Roeder added that this MED1 regulatory pathway fits into a broader trend where acetylation regulates transcription factors. His earlier research on the protein p53 helped establish this principle. Understanding these fundamental mechanisms allows researchers to identify pathways that could be targeted for therapeutic purposes.
The discovery of this molecular switch highlights the importance of basic research in uncovering potential new avenues for cancer treatment, offering hope for patients facing challenging diagnoses.
