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Review Open Access

Histone deacetylases: Function in tumor development and therapeutic prospects (Review)

  • Authors:
    • Runling Lin
    • Yu Zhang
    • Hong Li
    • Fan Liang
  • View Affiliations / Copyright

    Affiliations: Department of Biochemistry and Molecular Biology, School of Basic Medicine, Shandong Second Medical University, Weifang, Shandong 261000, P.R. China
    Copyright: © Lin et al. This is an open access article distributed under the terms of Creative Commons Attribution License.
  • Article Number: 144
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    Published online on: February 24, 2026
       https://doi.org/10.3892/ol.2026.15497
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Abstract

Histone deacetylases (HDACs), as key epigenetic regulators, serve a central role in tumorigenesis and progression by modulating chromatin architecture and gene transcription. In recent years, notable advances have been made in elucidating the pan‑cancer mechanisms of HDACs and their inhibitors (HDACis), as well as in performing clinical studies, with their antitumor activity becoming a major research focus. The present review summarized the classification and molecular mechanisms of HDACs alongside their roles in various malignancies including ovarian cancer, endometrial carcinoma, glioma, osteosarcoma and multiple myeloma. The present review specifically elaborated on the relationship between particular isoforms, such as HDAC3, HDAC5, HDAC7 and HDAC11, and tumor progression, detailing associated signaling pathways. The present review systematically evaluated the current clinical applications of HDACis, examining both monotherapy and combination therapy efficacy alongside existing challenges. Furthermore, the present review discussed recent progress in structural modifications aimed at enhancing selectivity while reducing toxicity, as well as novel targeting strategies. Concluding with perspectives on HDAC‑based therapies, the present review underscores the key importance of precision targeting and combinatorial approaches to improve patient outcomes in the future.

View Figures

Figure 1

Interaction between histone
deacetylases and tumor-related signaling pathways. HDACs can
interact with key signaling pathways such as NF-κB and p53, thereby
regulating the cellular response to stress and growth signals.
HDACs can also deacetylate components of the NF-κB pathway, thus
promoting the survival and proliferation of tumor cells. By
inhibiting the transcriptional activity of p53, HDACs enable cancer
cells to evade apoptosis. Additionally, HDACs can deacetylate
SATB1, thereby inhibiting tumor suppressor genes (↑, promotion).
HDACs, histone deacetylases; NF-κB, nuclear factor-κB; SATB1,
special AT-rich sequence-binding protein 1; Ac, acetylation.

Figure 2

Role of HDACs in ovarian cancer. In
serous ovarian cancer, HDAC9 promotes the expression levels of
TGF-β by deacetylating FOXO1 and increasing its nuclear
accumulation. The upregulated TGF-β enhances cell migration by
activating EMT. In non-serous ovarian cancer, HDAC9 inhibits EMT
and cell migration by deacetylating β-catenin and reducing its
nuclear localization (↑, promotion; ↓ inhibition). Clinical trials
have demonstrated that the efficacy of HDACis as a single-agent
therapy is limited, while the combination of HDACis with PARPis and
other drugs can improve the efficacy of cancer treatment and
overcome drug resistance. FOXO1, forkhead box protein O1; TGF-β,
transforming growth factor-β; HDACs, histone deacetylases; HDACis,
HDAC inhibitors; PARPis, poly(ADP-ribose) polymerase inhibitors;
EMT, epithelial-mesenchymal transition; TCF, transcription factor;
Ac, acetylation; CBP, CREB-binding protein; LEF, lymphoid
enhancer-binding factor.

Figure 3

Role of HDAC5 in lung adenocarcinoma.
HDAC5-mediated deacetylation of SATB1 reduces its transcriptional
activity. The downregulation of SATB1 activity can enhance the
migratory ability of lung adenocarcinoma cells, thereby promoting
tumor metastasis (↑, promotion). HDAC, histone deacetylase; SATB1,
special AT-rich sequence-binding protein 1; Ac, acetylation.

Figure 4

Role of HDAC7 in tumors. HDAC7 is a
key regulatory factor that promotes tumor growth, metastasis and
drug resistance, and its mechanism of action is closely related to
the regulation of the vascular microenvironment. In non-small cell
lung cancer, HDAC7 maintains the stability of β-catenin, promotes
its nuclear translocation, and subsequent binding to TCF4, thereby
activating the expression levels of FGF18. Inhibiting HDAC7 may
block this oncogenic signaling cascade. The regulatory role of
HDAC7 also extends to the tumor microenvironment, participating in
disease progression by influencing angiogenesis and immune
responses (↑, promotion). HDAC, histone deacetylase; TCF4,
transcription factor 4; FGF18, fibroblast growth factor 18.

Figure 5

Role of HDAC11 in tumors. In HCC, the
inhibition of miR-145-5p leads to an increase in HDAC11 levels,
which in turn enhances resistance to sorafenib and the metastatic
potential of HCC cells. However, inhibiting HDAC11 activity can
restore the level of miR-145-5p, rendering HCC cells sensitive to
sorafenib and reducing their metastatic ability (↑, promotion; ↓
inhibition). HDAC, histone deacetylase; HCC, hepatocellular
carcinoma; miR, microRNA; EMT, epithelial-mesenchymal
transition.
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Copy and paste a formatted citation
Spandidos Publications style
Lin R, Zhang Y, Li H and Liang F: <p>Histone deacetylases: Function in tumor development and therapeutic prospects (Review)</p>. Oncol Lett 31: 144, 2026.
APA
Lin, R., Zhang, Y., Li, H., & Liang, F. (2026). <p>Histone deacetylases: Function in tumor development and therapeutic prospects (Review)</p>. Oncology Letters, 31, 144. https://doi.org/10.3892/ol.2026.15497
MLA
Lin, R., Zhang, Y., Li, H., Liang, F."<p>Histone deacetylases: Function in tumor development and therapeutic prospects (Review)</p>". Oncology Letters 31.4 (2026): 144.
Chicago
Lin, R., Zhang, Y., Li, H., Liang, F."<p>Histone deacetylases: Function in tumor development and therapeutic prospects (Review)</p>". Oncology Letters 31, no. 4 (2026): 144. https://doi.org/10.3892/ol.2026.15497
Copy and paste a formatted citation
x
Spandidos Publications style
Lin R, Zhang Y, Li H and Liang F: <p>Histone deacetylases: Function in tumor development and therapeutic prospects (Review)</p>. Oncol Lett 31: 144, 2026.
APA
Lin, R., Zhang, Y., Li, H., & Liang, F. (2026). <p>Histone deacetylases: Function in tumor development and therapeutic prospects (Review)</p>. Oncology Letters, 31, 144. https://doi.org/10.3892/ol.2026.15497
MLA
Lin, R., Zhang, Y., Li, H., Liang, F."<p>Histone deacetylases: Function in tumor development and therapeutic prospects (Review)</p>". Oncology Letters 31.4 (2026): 144.
Chicago
Lin, R., Zhang, Y., Li, H., Liang, F."<p>Histone deacetylases: Function in tumor development and therapeutic prospects (Review)</p>". Oncology Letters 31, no. 4 (2026): 144. https://doi.org/10.3892/ol.2026.15497
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