UK scientists from The University of Birmingham have discovered how certain cancer cells can adapt and render cancer drugs ineffective. These drugs, known as histone deacetylase (HDAC) inhibitors, are designed to disrupt cancer cells’ genetic controls. Their research, published in Epigenetics and Chromatin, may help create new therapies focused on preventing tumors from overcoming HDAC inhibitors (HDACi).
Genes can be switched on or off via molecular tags that attach to DNA and transfer signals to tell the cell how to arrange the DNA. HDAC inhibitors are drugs that lead to an accumulation of certain molecular tags which can typically destroy cancer cells by making adjustments to gene activity. HDACs, or histone deacetylases, are enzymes that remove the molecular tags – specifically acetyl groups – from a histone. This leads to the tightening of DNA around the histones which transcriptionally silences chromatin. HDAC inhibitors are able to prevent this from happening, resulting in histone hyperacetylation and altered gene expression.
These HDAC inhibitors, however, are not successful in killing all cancer types. It’s striking that some cancer cells can tolerate the significant hyperacetylation of core histones and various proteins as a result of HDAC inhibitors and can continue to proliferate. The researchers set out to study the underlying epigenetic mechanisms which may offer an explanation.
The researchers suggest that these HDAC inhibitor resistant cancers activate a built-in, coordinated survival response which minimizes protein hyperacetylation, ultimately slowing growth and re-balancing patterns of gene expression to promote cell survival. Unexpectedly, the researchers found that “the response involves a precisely timed increase in H3K27me3 at transcription start sites, but little or no increase in histone acetylation, whose role seems to be to provide a stable chromatin environment that allows transcription to be modified by other factors.”
Their results may help determine whether or not HDAC inhibitor drugs would be successful for certain patients. In the future, cancer therapies could be developed to overcome this tumor survival mechanism that resists the effects of HDAC inhibitors.
Dr. John Halsall, the lead author and Cancer Research UK scientist from the University of Birmingham, explained, “Our work has shown that some cancer cells can survive the gene damage caused by HDAC inhibitor drugs, so we’ve unveiled a new layer of the cancer cell’s defense that we need to target to destroy tumors.”
Speaking to the future implications of these results, he said, “If we work out exactly which types of cancer are vulnerable to these drugs we can use them in a smarter way to treat patients more effectively.”
Cancer Research UK’s science information manager, Dr. Kat Arney, said, “Working out how genes are switched on and off in cancer is vital if we’re to truly understand and beat the disease. This study could help us tailor how we use HDAC inhibitors so that more patients could benefit from them, and we’ll continue to work towards finding more effective ways to target cancer’s control mechanisms in the future.”
Source: Halsall, J.A., Turan, N., Wiersma, M., Turner, B.M. (2015). Cells adapt to the epigenomic disruption caused by histone deacetylase inhibitors through a coordinated, chromatin-mediated transcriptional response. Epigenetics & Chromatin, 8:29.
Reference: Cancer Research UK. Scientists discover how cells overpower cancer drug. 16 Sep 2015. Web.