Researchers at Baylor College of Medicine and its partner institutions are challenging conventional understanding of how cancer drugs called histone deacetylase (HDAC) inhibitors work. Scientists have believed for decades that these drugs inhibit HDAC enzymes, which promote cancer development by turning genes on and off.
Current studies suggest that HDAC inhibitors do not necessarily rely solely on HDAC inhibition and may also affect other pathways. This study Signal transduction and targeted therapy highlight the importance of identifying the true molecular targets of HDAC inhibitors as the next step to improve cancer therapy.
DNA within cells is wrapped in proteins called histones. Chemical changes to histones, such as adding or removing acetyl chemical groups, are thought to determine which genes are activated. ”
Zheng Sun, Ph.D., corresponding author, associate professor of medicine, endocrinology, diabetes and metabolism, and member of Baylor’s Dan L. Duncan Comprehensive Cancer Center
HDACs remove acetyl groups from histones. The general idea is that increasing histone acetylation with HDAC inhibitors promotes beneficial gene expression changes that may slow cancer progression or lead to cancer death.
“However, there are also studies that do not support this idea,” Sun said. “In some situations, HDACs do not promote cancer, but instead act as tumor suppressors. HDAC inhibitors can increase histone acetylation, but have only a modest effect on gene expression.”
In the current study, Sun and colleagues applied multiple unbiased approaches to first investigate the relationship between HDACs and different types of cancer, and then investigate the role of HDACs in the anticancer activity of HDAC inhibitors. They conducted these studies in multiple solid tumor models where HDAC inhibitors are being clinically tested.
“Our unbiased bioinformatics analysis showed that HDACs are not always associated with cancer growth. Different types of HDACs and their levels are not consistently correlated with most cancers or patient survival,” said first author Chaitra Rai, Ph.D., a postdoctoral fellow in the Sun lab. “We also found that the anticancer effects of the HDAC inhibitor FK228 were independent of its ability to inhibit HDAC in the mouse model. For HDAC inhibitors that block the HDAC family, we eliminated their ability to inhibit the enzyme, but in the mouse model, the inhibitor retained most of its anticancer effects.”
Therefore, although some HDAC inhibitors may act through HDACs in certain situations, this result suggests that this mechanism is not as universal as previously assumed. “We propose that HDAC inhibitors may also interfere with other proteins, and targeting such proteins may suppress cancer,” Sun said. “Identifying other molecular targets for HDAC inhibitors is an important step toward improving cancer treatment.”
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Baylor College of Medicine
Reference magazines:
DOI: 10.1038/s41392-026-02698-1
