Histone deacetylase turnover and recovery in sulforaphane-treated colon cancer cells: competing actions of 14-3-3 and Pin1 in HDAC3/SMRT corepressor complex dissociation/reassembly. Mol Cancer 10:68

Linus Pauling Institute, Oregon State University, Corvallis, OR 97331-6512, USA.
Molecular Cancer (Impact Factor: 4.26). 05/2011; 10(1):68. DOI: 10.1186/1476-4598-10-68
Source: PubMed


Histone deacetylase (HDAC) inhibitors are currently undergoing clinical evaluation as anti-cancer agents. Dietary constituents share certain properties of HDAC inhibitor drugs, including the ability to induce global histone acetylation, turn-on epigenetically-silenced genes, and trigger cell cycle arrest, apoptosis, or differentiation in cancer cells. One such example is sulforaphane (SFN), an isothiocyanate derived from the glucosinolate precursor glucoraphanin, which is abundant in broccoli. Here, we examined the time-course and reversibility of SFN-induced HDAC changes in human colon cancer cells.
Cells underwent progressive G2/M arrest over the period 6-72 h after SFN treatment, during which time HDAC activity increased in the vehicle-treated controls but not in SFN-treated cells. There was a time-dependent loss of class I and selected class II HDAC proteins, with HDAC3 depletion detected ahead of other HDACs. Mechanism studies revealed no apparent effect of calpain, proteasome, protease or caspase inhibitors, but HDAC3 was rescued by cycloheximide or actinomycin D treatment. Among the protein partners implicated in the HDAC3 turnover mechanism, silencing mediator for retinoid and thyroid hormone receptors (SMRT) was phosphorylated in the nucleus within 6 h of SFN treatment, as was HDAC3 itself. Co-immunoprecipitation assays revealed SFN-induced dissociation of HDAC3/SMRT complexes coinciding with increased binding of HDAC3 to 14-3-3 and peptidyl-prolyl cis/trans isomerase 1 (Pin1). Pin1 knockdown blocked the SFN-induced loss of HDAC3. Finally, SFN treatment for 6 or 24 h followed by SFN removal from the culture media led to complete recovery of HDAC activity and HDAC protein expression, during which time cells were released from G2/M arrest.
The current investigation supports a model in which protein kinase CK2 phosphorylates SMRT and HDAC3 in the nucleus, resulting in dissociation of the corepressor complex and enhanced binding of HDAC3 to 14-3-3 or Pin1. In the cytoplasm, release of HDAC3 from 14-3-3 followed by nuclear import is postulated to compete with a Pin1 pathway that directs HDAC3 for degradation. The latter pathway predominates in colon cancer cells exposed continuously to SFN, whereas the former pathway is likely to be favored when SFN has been removed within 24 h, allowing recovery from cell cycle arrest.

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Available from: Praveen Rajendran, Oct 07, 2015
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    • "Ellagic acid, a polyphenol found in a lot of fruit and vegetables increased the expression of HDAC9 in human adipogenic stem cells thereby attenuating adipocyte differentiation through modulation of CARM1 activity [198]. In accordance with the downregulation of HDAC4 and HDAC8 by cocoa flavanol metabolites, curcumin, sulforaphane, apigenin, green tea polyphenols and indoles also could reduce transcript and/or protein levels of HDAC4 and HDAC8 [199] [200] [201] [202] [203] [204] [205] [206] [207] [208] [209] [210]. One study however, demonstrated an increase in HDAC4 and HDAC8 protein expression after treating the human prostate cancer (LNCaP) cells with curcumin [211]. "
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    • "It is possible that DIM may specifically alter protein turnover pathways that specifically control HDAC2 protein levels post-translationally. In colon cancer cells, the phytochemical sulforaphane has been shown to specifically decrease HDAC3 protein levels, with no change in mRNA levels by inducing HDAC3 degradation through post-translational phosphorylation of the protein (Rajendran et al., 2011). DIM-induced down regulation of HDAC2 in prostate cancer cells is consistent with a previous report in colon cancer cells that also observed a DIM-induced down regulation of HDAC2 (Bhatnagar et al., 2009; Li et al., 2010). "
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