Study proposes reconsidering how histone deacetylase inhibitors work in cancer treatment
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Researchers at Baylor College of Medicine and collaborating institutions are challenging the traditional understanding of how cancer drugs called histone deacetylase (HDAC) inhibitors function. For decades, scientists believed that these drugs blocked HDAC enzymes, which drive cancer development by altering how genes are turned on and off.
The current study suggests that HDAC inhibitors do not necessarily rely solely on HDAC inhibition but also may 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 treatment.
"The DNA inside cells is wrapped around proteins called histones. Chemical changes to histones, such as adding or removing acetyl chemical groups, are believed to determine which genes are active," said corresponding author Dr. Zheng Sun, 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 has been that increasing histone acetylation with HDAC inhibitors promotes beneficial gene expression changes that may slow cancer or lead to cancer cell death.
"Yet, some findings do not support this idea," Sun said. "In some contexts, HDACs do not promote cancer, but act as tumor suppressors instead. Sometimes HDAC inhibitors can increase histone acetylation but with only moderate effects on gene expression."
In the current study, Sun and his colleagues applied multiple unbiased approaches to investigate, first, the relationship between HDACs and various cancer types and, second, the role of HDACs in the anticancer activity of the HDAC inhibitors. They conducted these studies in multiple solid tumor models in which HDAC inhibitors are being tested clinically.
"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," said first author Dr. Chaitra Rai, a postdoctoral fellow in the Sun lab.
"We also found that the anticancer effects of HDAC inhibitor FK228 were independent of its ability to inhibit HDACs in a mouse model. On HDAC inhibitors that block a family of HDACs, we eliminated their ability to inhibit the enzymes, yet the inhibitors retained most of their anticancer effects in a mouse model."
Therefore, although some HDAC inhibitors may act through HDACs in certain contexts, the results suggest that this mechanism is not as universal as previously assumed.
"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."
More information
Chaitra Rai et al, Histone deacetylase enzyme activity is not the universal anticancer target of HDAC inhibitors, Signal Transduction and Targeted Therapy (2026). DOI: 10.1038/s41392-026-02698-1
Key medical concepts
Histone Deacetylase InhibitorsHistone Deacetylasesromidepsin
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OncologyClinical pharmacology Provided by Baylor College of Medicine Who's behind this story?
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Citation: Study proposes reconsidering how histone deacetylase inhibitors work in cancer treatment (2026, June 7) retrieved 7 June 2026 from https://medicalxpress.com/news/2026-06-reconsidering-histone-deacetylase-inhibitors-cancer.html This document is subject to copyright. Apart from any fair dealing for the purpose of private study or research, no part may be reproduced without the written permission. The content is provided for information purposes only.