Related Experiment Video
Updated: Feb 16, 2026
Assays for Validating Histone Acetyltransferase Inhibitors
Published on: August 6, 2020
Validation of histone deacetylase 3 as a therapeutic target in castration-resistant prostate cancer
Abigail B McLeod1, James P Stice1, Suzanne E Wardell1
1Department of Pharmacology and Cancer Biology, Duke University School of Medicine, Durham, North Carolina.
Background:
Whereas the androgen receptor (AR) signaling axis remains a therapeutic target in castration-resistant prostate cancer (CRPC), the emergence of AR mutations and splice variants as mechanisms underlying resistance to contemporary inhibitors of this pathway highlights the need for new therapeutic approaches to target this disease. Of significance in this regard is the considerable preclinical data, indicating that histone deacetylase (HDAC) inhibitors may have utility in the treatment of CRPC. However, the results of clinical studies using HDAC inhibitors (directed against HDAC1, 2, 3, and 8) in CRPC are equivocal, a result that some have attributed to their ability to induce an epithelial to mesenchymal transition (EMT) and neuroendocrine differentiation. We posited that it might be possible to uncouple the beneficial effects of HDAC inhibitors on AR signaling from their undesired activities by targeting specific HDACs as opposed to using the pan-inhibitor strategy that has been employed to date.
Methods:
The relative abilities of pan- and selective-Class I HDAC inhibitors to attenuate AR-mediated target gene expression and proliferation were assessed in several prostate cancer cell lines. Small interfering RNA (siRNA)-mediated knockdown approaches were used to confirm the importance of of HDAC 1, 2, and 3 expression in these processes. Further, the ability of each HDAC inhibitor to induce the expression of EMT markers (RNA and protein) and EMT-like phenotype(s) (migration) were also assessed. The anti-tumor efficacy of a HDAC3-selective inhibitor, RGFP966, was compared to the pan-HDAC inhibitor Suberoylanilide Hydroxamic Acid (SAHA) in the 22Rv1 xenograft model.
Results:
Using genetic and pharmacological approaches we demonstrated that a useful inhibition of AR transcriptional activity, absent the induction of EMT, could be achieved by specifically inhibiting HDAC3. Significantly, we also determined that HDAC3 inhibitors blocked the activity of the constitutively active AR V7-splice variant and inhibited the growth of xenograft tumors expressing this protein.
Conclusions:
Our studies provide strong rationale for the near-term development of specific HDAC3 inhibitors for the treatment of CRPC.
Insights
Targeting histone deacetylase 3 (HDAC3) specifically inhibits androgen receptor (AR) activity and prostate cancer growth without inducing resistance mechanisms. This approach offers a promising new strategy for treating castration-resistant prostate cancer (CRPC).
Area of Science:
- Oncology
- Molecular Biology
- Drug Discovery
Background:
- Castration-resistant prostate cancer (CRPC) remains a challenge, with resistance to androgen receptor (AR) inhibitors driven by AR mutations and splice variants.
- Histone deacetylase (HDAC) inhibitors show preclinical promise for CRPC, but clinical results are equivocal, potentially due to inducing epithelial-to-mesenchymal transition (EMT) and neuroendocrine differentiation.
- Targeting specific HDACs, rather than using broad-spectrum inhibitors, may decouple beneficial effects on AR signaling from detrimental side effects.
Purpose of the Study:
- To evaluate the efficacy of selective versus pan-HDAC inhibitors in attenuating AR signaling and proliferation in prostate cancer.
- To determine if specific HDAC inhibition can overcome resistance mechanisms associated with AR mutations and splice variants.
- To assess the potential of HDAC inhibitors to induce or prevent epithelial-to-mesenchymal transition (EMT) and neuroendocrine differentiation.
Main Methods:
- Assessed AR-mediated gene expression and cell proliferation using pan- and selective-Class I HDAC inhibitors in prostate cancer cell lines.
- Utilized siRNA to confirm the role of HDAC1, 2, and 3 in these processes.
- Evaluated the induction of EMT markers and phenotypes (migration) and compared the in vivo efficacy of a HDAC3-selective inhibitor (RGFP966) versus a pan-HDAC inhibitor (SAHA) in a xenograft model.
Main Results:
- Specific inhibition of HDAC3 effectively suppressed AR transcriptional activity without inducing EMT.
- HDAC3 inhibitors demonstrated efficacy against the AR V7-splice variant, a common resistance mechanism.
- A HDAC3-selective inhibitor significantly inhibited tumor growth in a preclinical xenograft model.
Conclusions:
- Specific HDAC3 inhibition represents a viable therapeutic strategy for CRPC, offering AR pathway modulation without inducing resistance.
- HDAC3 inhibitors show particular promise for treating CRPC driven by AR splice variants like AR-V7.
- These findings provide a strong rationale for the clinical development of selective HDAC3 inhibitors for CRPC treatment.
More Related Videos
07:25A Bioluminescent and Fluorescent Orthotopic Syngeneic Murine Model of Androgen-dependent and Castration-resistant Prostate Cancer
Published on: March 6, 2018
12:13Sequencing Small Non-coding RNA from Formalin-fixed Tissues and Serum-derived Exosomes from Castration-resistant Prostate Cancer Patients
Published on: November 19, 2019