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Histone deacetylase enzyme activity is not the universal anti-cancer target of HDAC inhibitors [RNA-seq_MC38]

ABSTRACT: As a family of anti-cancer drugs, histone deacetylase inhibitors (HDIs) show efficacies against a wide range of cancers, but their mechanism of action is unclear. Here, we performed unbiased bioinformatics analysis and found that genetic variants or expression levels of HDACs do not correlate with the carcinogenesis of most cancer types and do not predict cancer patient survival. Whole-genome CRISPR library screens did not identify HDACs as genes affecting cellular responses to HDIs such as SAHA or MS-275. Overexpression of dominant-negative, catalytically inactive Class I HDACs (HDAC1, 2, 3, and 8) caused a similar degree of histone hyperacetylation as Class I-specific HDI FK228 in cancer cell lines without similar anti-cancer effects, transcriptomic changes, or cellular responses to FK228. The anti-cancer effects of FK228 can be further dissociated from the histone hyperacetylation in an in-situ liver cancer mouse model. Importantly, chemical manipulations of several pan-HDIs abolished HDAC-inhibiting activity but retained the majority of anti-cancer effects in a mouse xenograft cancer model. These results suggest that HDAC enzyme activity is not a universal de facto target of HDIs for their anti-cancer efficacy. These findings have profound implications for understanding the pharmacodynamics of HDIs and developing next-generation compounds for this promising family of anti-cancer drugs.

ORGANISM(S): Mus musculus

PROVIDER: GSE288240 | GEO | 2026/03/27

REPOSITORIES: GEO

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Project description:Sensing of microbial products by innate immune cells skew their transcriptional program to optimize anti-microbial defences. Chromatin remodeling by histone deacetylases (HDACs) plays a fundamental role in tailoring gene expression. HDAC inhibitors are among the most promising anti-cancer drugs and possess intrinsic anti-inflammatory properties. Yet, the influence of HDAC inhibition on innate immune responses to microbial infection is unknown. Here we show that HDAC inhibitors repress the expression of less than 10% of the genes expressed at baseline in BM-derived macrophages. In sharp contrast, HDAC inhibitors strongly interfere with transcriptome remodeling induced by LPS and Pam3CSK4, affecting the expression of 30-70% of genes modulated by microbial stimuli. Strikingly, HDAC inhibitors target the expression of numerous genes involved in anti-microbial host defences, encoding for microbial sensors, cytokines, chemokines, growth factors and their receptors, adhesion and signaling molecules, and molecules involved in antigen processing and presentation. At the molecular level, HDAC inhibitors do not impair mitogen-activated protein kinase, NF-kB, interferon-related factor signal and STAT1 transduction pathways, but inhibit NF-kB p65 recruitment to the promoter region of HDAC inhibitor-sensitive genes. HDAC inhibitors also inhibit the response of mouse and human DCs, splenocytes and whole blood to a broad range of microbial products and microorganisms. In agreement with these in vitro findings, HDAC inhibitors increase bacterial burden and sensitize mice to sub-lethal infection with Klebsiella pneumoniae and Candida albicans. Conversely, HDAC inhibitors confer protection in models of Pam3CSK4-induced fulminant toxic shock and severe sepsis following cecal ligation and puncture. Overall, these data substantiate the concept of immunomodulation by HDAC inhibitors, and suggest that these drugs could represent efficacious adjunctive therapy of severe sepsis. Mus musculus cells were grown in presence of LPS or LPS + TSA and pam or pam + TSA and hybrydised against a cRNA pool UMRR (from Mus musculus cells).

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Histone deacetylase enzyme activity is not the universal anti-cancer target of HDAC inhibitors [RNA-seq_MC38]

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OmicsDI is part of the ELIXIR infrastructure

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­Histone deacetylase enzyme activity is not the universal anti-cancer target of HDAC inhibitors [RNA-seq_MC38]

Dataset's files

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OmicsDI is part of the ELIXIR infrastructure

Tweets

Histone deacetylase enzyme activity is not the universal anti-cancer target of HDAC inhibitors [RNA-seq_MC38]