Clues to DNA Packing Can Help Better Target Cancer Cells

Histones spooling DNA. Credit: OIST (Okinawa Institute of Science and Technology Graduate University)

Key Points: 

• A new study uses egg “soup” to explain how DNA packing works in human cells.
• They were surprised to find DNA packing was delayed when HDAC1 was inhibited.
• Targeting HDAC proteins with selective inhibitors can aid in creating more successful cancer treatments.

Stretched end to end, one strand of DNA extends approximately 6.5 feet. Each single cell can condense this much DNA by winding it around proteins called histones. This is a good thing, except when it comes to cancer cells, which are more sensitive to the packing and unpacking of DNA since they divide faster than healthy, normal cells.

A Medical University of South Carolina research team led by David Long reports in the Journal of Biological Chemistry that the protein HDAC1, plays a larger role in packing DNA around histones than previously thought.

Long developed a system using an extract made from the eggs of African clawed frogs to better understand which proteins play a role in winding up DNA. The extract system includes all the proteins within the nucleus but removes the DNA. The team wanted to see what happened when they used inhibitors that target different groups of HDAC proteins. Currently, multiple HDAC inhibitors are being used in clinical trials for cancer treatment.

For their study, the researchers developed tools to target either HDAC1 or HDAC2 specifically. They thought the effects on DNA packing would be similar regardless of which protein they targeted. Instead, DNA packing was delayed only when HDAC1 was inhibited. This surprised the researchers, leading them to explore further how HDAC1 interacts with different proteins than HDAC2 to complete its job.

The study’s findings are important for several reasons. First, the extract system used in Long’s lab is novel and can be used to answer questions that are difficult to address using traditional cell or animal models. Second, future cancer therapies could focus on developing inhibitors that specifically target individual HDAC proteins. The researchers found that HDAC1, not HDAC2, is the major driver of DNA packing in some contexts, so targeting only HDAC1 could be more effective and have fewer side effects during treatment.

“These selective inhibitors are a great way to target cancer cells,” said Long. “Cancer cells grow quickly, so if we can disrupt how they’re able to pack and unpack DNA, that will make them more sensitive to cell death.”