Baylor Team Questions How HDAC Inhibitors Actually Work

For decades, the scientific community has operated on a straightforward assumption about histone deacetylase (HDAC) inhibitors: these cancer drugs work by blocking HDAC enzymes. A new study from Baylor College of Medicine and collaborating institutions challenges that assumption, suggesting the picture is considerably more complicated.

The research, published in Signal Transduction and Targeted Therapy, examined both the relationship between HDACs and various cancer types, and whether HDAC inhibition is actually responsible for the anti-cancer activity of these drugs. 

To understand why this matters, some background is useful. DNA inside cells is wrapped around proteins called histones, and chemical modifications to those histones—such as adding or removing acetyl groups—help determine which genes are active. HDACs remove acetyl groups from histones, and the prevailing idea has been that HDAC inhibitors, by blocking this removal, increase histone acetylation in ways that slow cancer growth or trigger cancer cell death.

But according to corresponding author Zheng Sun, some findings don't support this model. "In some contexts, HDACs do not promote cancer, but act as tumor suppressors instead," Sun said. "Sometimes HDAC inhibitors can increase histone acetylation but with only moderate effects on gene expression."

The research team applied multiple unbiased approaches to investigate these questions across solid tumor models where HDAC inhibitors are currently being tested clinically. First author Chaitra Rai described what the analyses revealed: "Our unbiased bioinformatics analyses showed that HDACs are not always associated with cancer growth—different types of HDACs or their levels do not correlate consistently with most cancers or patient survival."

The team also found that the anti-cancer effects of HDAC inhibitor FK228 were independent of its ability to inhibit HDACs in a mouse model. When the researchers eliminated the enzyme-inhibiting ability of HDAC inhibitors that block a family of HDACs, those compounds still retained most of their anti-cancer effects.

Taken together, the findings suggest that HDAC inhibition may not be the universal mechanism it was assumed to be. "We propose 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 treatment."