Differential effects of garcinol and curcumin on histone and p53 modifications in tumour cells

Abstract

BackgroundPost-translational modifications (PTMs) of histones and other proteins are perturbed in tumours. For example, reduced levels of acetylated H4K16 and trimethylated H4K20 are associated with high tumour grade and poor survival in breast cancer. Drug-like molecules that can reprogram selected histone PTMs in tumour cells are therefore of interest as potential cancer chemopreventive agents. In this study we assessed the effects of the phytocompounds garcinol and curcumin on histone and p53 modification in cancer cells, focussing on the breast tumour cell line MCF7.MethodsCell viability/proliferation assays, cell cycle analysis by flow cytometry, immunodetection of specific histone and p53 acetylation marks, western blotting, siRNA and RT-qPCR.ResultsAlthough treatment with curcumin, garcinol or the garcinol derivative LTK-14 hampered MCF7 cell proliferation, differential effects of these compounds on histone modifications were observed. Garcinol treatment resulted in a strong reduction in H3K18 acetylation, which is required for S phase progression. Similar effects of garcinol on H3K18 acetylation were observed in the osteosarcoma cells lines U2OS and SaOS2. In contrast, global levels of acetylated H4K16 and trimethylated H4K20 in MCF7 cells were elevated after garcinol treatment. This was accompanied by upregulation of DNA damage signalling markers such as γH2A.X, H3K56Ac, p53 and TIP60. In contrast, exposure of MCF7 cells to curcumin resulted in increased global levels of acetylated H3K18 and H4K16, and was less effective in inducing DNA damage markers. In addition to its effects on histone modifications, garcinol was found to block CBP/p300-mediated acetylation of the C-terminal activation domain of p53, but resulted in enhanced acetylation of p53K120, and accumulation of p53 in the cytoplasmic compartment. Finally, we show that the elevation of H4K20Me3 levels by garcinol correlated with increased expression of SUV420H2, and was prevented by siRNA targeting of SUV420H2.ConclusionIn summary, although garcinol and curcumin can both inhibit histone acetyltransferase activities, our results show that these compounds have differential effects on cancer cells in culture. Garcinol treatment alters expression of chromatin modifying enzymes in MCF7 cells, resulting in reprogramming of key histone and p53 PTMs and growth arrest, underscoring its potential as a cancer chemopreventive agent.

Garcinol: Current status of its anti-oxidative, anti-inflammatory and anti-cancer effects

“…Therefore, extensive formulation strategies have been employed to improve its bioavailability [74]. Garcinol, like curcumin, is a natural compound that has been extensively studied and suggested to have beneficial therapeutic effects [28]. Thus, lessons must be learned from previous examples in order to progress studies of garcinol to the clinical phase.…”

Acetyltransferases (HATs) as Targets for Neurological Therapeutics

“…The first reported HAT inhibitor from natural sources was obtained from Garcinia indica. Garcinol from G. indica nonspecifically inhibits p300 and PCAF HAT activity, but, recently, this inhibitor has shown great promise as a potent anticancer drug [66]. Owing to the specific focus of this article, we shall confine the review to HAT activators and their therapeutic potential.…”

The effective combination therapy against human osteosarcoma: doxorubicin plus curcumin co-encapsulated lipid-coated polymeric nanoparticulate drug delivery system

“…Tumor inhibitory activity is attributed to its inhibiting NF-kB and its up-regulation of p53 expression (the mechanism of anti-multidrug resistance); and its action on tumor necrosis factor (TNF-a), vascular endothelial growth factor (VEGF), cyclooxygenase, matrix metalloproteinase, etc. (Brennan & O'Neill, 1998;Collins et al, 2013;Chang et al, 2015). However, its poor aqueous solubility and low systemic bioavailability has become the obstacle to its clinical application.…”