Researchers at Baylor College of Medicine and partner institutions are challenging the traditional understanding of how cancer drugs called histone deacetylase (HDAC) inhibitors work. For decades, scientists believed that these drugs block HDAC enzymes, which drive cancer growth by changing the way genes are turned on and off.
The current study suggests that HDAC inhibitors do not necessarily rely exclusively on HDAC inhibition but may also affect other pathways. The study, published in Signal Transduction and Targeted Therapy highlights the importance of identifying genuine molecular targets of HDAC inhibitors as a next step to improve cancer therapy.
The DNA inside cells is wrapped around proteins called histones. “Chemical changes in histones, such as the addition or removal of chemical acetyl groups, are thought to determine which genes are active.”
Dr. Zheng Sun, corresponding author, associate professor of medicine – endocrinology, diabetes and metabolism, and member of the Dan L Duncan Comprehensive Cancer Center at Baylor
HDACs remove acetyl groups from histones. The prevailing idea was that increasing histone acetylation with HDAC inhibitors promotes beneficial changes in gene expression that may slow cancer or lead to cancer death.
“However, some findings do not support this idea,” Sun said. “In some contexts, HDACs do not promote cancer, but act as tumor suppressors. Sometimes HDAC inhibitors can increase histone acetylation but with only modest effects on gene expression.”
In the current study, Sun and colleagues applied multiple unbiased approaches to investigate, first, the relationship between HDACs and various types of cancer and, second, the role of HDACs in the antitumor activity of HDAC inhibitors. They conducted these studies in multiple solid tumor models in which HDAC inhibitors are clinically tested.
“Our unbiased bioinformatics analyzes showed that HDACs are not always associated with cancer development – different types of HDACs or their levels are not consistently associated with most cancers or patient survival,” said first author Dr. Chaitra Rai, a postdoctoral fellow in the Sun lab. “We also found that the antitumor effects of the HDAC inhibitor FK228 were independent of its ability to inhibit HDACs in a mouse model. In HDAC inhibitors that block a family of HDACs, we eliminated their ability to inhibit the enzymes, yet the inhibitors retained most of their antitumor effects in a mouse model.”
Therefore, although some HDAC inhibitors may act through HDACs in some contexts, the results suggest that this mechanism is not as universal as previously assumed. “We suggest that HDAC inhibitors may also interfere with other proteins, and that targeting such proteins may suppress cancer,” Sun said. “Identifying other molecular targets of HDAC inhibitors represents an important step toward improving cancer therapy.”
