Histone Deacetylase Enzyme Activity Is Not the Universal Anticancer Target of HDAC Inhibitors

Authors

• Chaitra Rai
• Hang Ruan
• Xue Li
• Wenbo Li
• Hyun-Hwan Jeong
• Chengchuang Song
• Panpan Liu
• Yingjie Chang
• Hao Fang
• Udhaya Kumar S
• Yuxiang Sun
• M James You
• Dongyin Guan
• Zhandong Liu
• Leng Han
• Xuben Hou
• Zheng Sun

Language

English

Publication Date

6-5-2026

Journal

Signal Transduction and Targeted Therapy

DOI

10.1038/s41392-026-02698-1

PMID

42248845

PMCID

PMC13241515

PubMedCentral® Posted Date

6-5-2026

PubMedCentral® Full Text Version

Post-print

Abstract

Histone deacetylase inhibitors (HDIs) are approved for treating hematologic cancers and are currently being evaluated in hundreds of clinical trials for various cancers and other diseases, although their mechanisms of action remain poorly understood. Here, our unbiased bioinformatics analyses found that, for most cancer types, expression levels or genetic variants of histone deacetylase (HDACs) do not consistently correlate with carcinogenesis, do not predict cancer patient survival, and do not associate with cellular responses to HDIs. Whole-genome CRISPR library screens did not identify HDACs as genes affecting cellular responses to HDIs. Overexpression of dominant-negative Class I HDACs causes similar protein hyperacetylation as Class I-specific HDI FK228, but does not have similar cytotoxic or transcriptomic effects as FK228 in vitro, and does not alter the anticancer effects of FK228 in vivo in a liver cancer mouse model. Chemical manipulations of a pan-HDI SAHA can abolish its HDAC-inhibiting activity without altering its anticancer effects in vivo in an allograft colon cancer mouse model. These results suggest that HDAC enzyme activity is not necessarily the de facto target of HDIs for their anticancer effects. This finding encourages a shift away from a narrow focus on HDACs for understanding HDIs' pharmacodynamics, opening new avenues for developing next-generation compounds for cancers and beyond.

Keywords

Histone Deacetylase Inhibitors, Animals, Humans, Histone Deacetylases, Mice, Depsipeptides, Liver Neoplasms, Cell Line, Tumor, Cancer, Cancer genetics

Published Open-Access

yes

Recommended Citation

Rai, Chaitra; Ruan, Hang; Li, Xue; et al., "Histone Deacetylase Enzyme Activity Is Not the Universal Anticancer Target of HDAC Inhibitors" (2026). Faculty, Staff and Students Publications. 6916.
https://digitalcommons.library.tmc.edu/baylor_docs/6916