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Assays for Validating Histone Acetyltransferase Inhibitors
Published on: August 6, 2020
Sulforaphane inhibits histone deacetylase activity in BPH-1, LnCaP and PC-3 prostate epithelial cells
Melinda C Myzak1, Karin Hardin, Rong Wang
1Linus Pauling Institute, Molecular and Cellular Biology Program, Department of Nutrition and Exercise Sciences, Oregon State University, Corvallis, OR 97331, USA.
Abstract:
Sulforaphane (SFN), an isothiocyanate first isolated from broccoli, exhibits chemopreventive properties in prostate cancer cells through mechanisms that are poorly understood. We recently reported on a novel mechanism of chemoprotection by SFN in human colon cancer cells, namely the inhibition of histone deacetylase (HDAC). Here, we show that addition of 15 microM SFN also inhibited HDAC activity by 40, 30 and 40% in BPH-1, LnCaP and PC-3 prostate epithelial cells, respectively. The inhibition of HDAC was accompanied by a 50-100% increase in acetylated histones in all three prostate cell lines, and in BPH-1 cells treated with SFN there was enhanced interaction of acetylated histone H4 with the promoter region of the P21 gene and the bax gene. A corresponding 1.5- to 2-fold increase was seen for p21Cip1/Waf1 and Bax protein expression, consistent with previous studies using HDAC inhibitors, such as trichostatin A. The downstream events included cell cycle arrest and activation of apoptosis, as evidenced by changes in cell cycle kinetics and induction of multi-caspase activity. These findings provide new insight into the mechanisms of SFN action in benign prostate hyperplasia, androgen-dependent prostate cancer and androgen-independent prostate cancer cells, and they suggest a novel approach to chemoprotection and chemotherapy of prostate cancer through the inhibition of HDAC.
Insights
Sulforaphane (SFN), derived from broccoli, inhibits histone deacetylase (HDAC) in prostate cells. This mechanism promotes cell cycle arrest and apoptosis, suggesting SFN as a novel chemoprotective agent for prostate cancer.
Area of Science:
- Biochemistry
- Molecular Biology
- Oncology
Background:
- Sulforaphane (SFN), a broccoli-derived isothiocyanate, shows chemopreventive potential in prostate cancer.
- The precise mechanisms of SFN's action in prostate cancer remain incompletely understood.
- Previous research identified SFN's inhibition of histone deacetylase (HDAC) in colon cancer cells.
Purpose of the Study:
- To investigate the effect of SFN on HDAC activity in various prostate epithelial cell lines.
- To elucidate the downstream molecular events triggered by SFN-induced HDAC inhibition in prostate cells.
- To explore the potential of SFN as a novel therapeutic strategy for prostate cancer via HDAC inhibition.
Main Methods:
- Treatment of BPH-1, LnCaP, and PC-3 prostate cells with 15 microM SFN.
- Assay of HDAC activity and quantification of acetylated histones.
- Analysis of histone-promoter interactions (acetylated histone H4 with P21 and bax promoters).
- Measurement of p21Cip1/Waf1 and Bax protein expression.
- Assessment of cell cycle kinetics and multi-caspase activity to evaluate apoptosis.
Main Results:
- SFN significantly inhibited HDAC activity in all tested prostate cell lines (BPH-1, LnCaP, PC-3).
- Increased levels of acetylated histones were observed in SFN-treated prostate cells.
- Enhanced interaction of acetylated histone H4 with P21 and bax gene promoters was noted in BPH-1 cells.
- SFN treatment led to increased p21Cip1/Waf1 and Bax protein expression.
- Downstream effects included cell cycle arrest and activation of apoptosis.
Conclusions:
- SFN effectively inhibits HDAC activity in benign and malignant prostate epithelial cells.
- SFN-mediated HDAC inhibition influences key gene expression (p21, bax) and downstream apoptotic pathways.
- These findings support a novel mechanism for SFN's chemoprotective and potential chemotherapeutic effects in prostate cancer through HDAC inhibition.
