Green tea–induced epigenetic reactivation of tissue inhibitor of matrix metalloproteinase‐3 suppresses prostate cancer progression through histone‐modifying enzymes

Abstract

Green tea polyphenols (GTPs) and their major constituent, epigallocatechin‐3‐gallate (EGCG), have been reported to demonstrate many interesting biological activities, including anticancer properties. Recent studies on prostate cancer provide strong evidence that epigenetic mechanisms are major players in the regulation of matrix metalloproteinases (MMPs) and their binding partner tissue inhibitor of MMPs (TIMPs) involved in prostate cancer progression. Here we demonstrate that GTP/EGCG mediate epigenetic reactivation of TIMP‐3 that plays a key role in suppressing invasiveness and cancer progression. Treatment of human prostate cancer DUPRO and LNCaP cells with 10 µg/mL GTP and 20 µM EGCG induced TIMP‐3 mRNA and protein expression. This transcriptional activation of TIMP‐3 was associated with the decrease in the expression of both enhancers of zeste homolog 2 (EZH2) and its catalytic product trimethylation of histone H3 at lysine 27 (H3K27me3) repressive marks at the TIMP‐3 promoter with an accompanying increase in histone H3K9/18 acetylation. In addition, GTP/EGCG treatment significantly reduced class I histone deacetylase (HDAC) activity/expression and EZH2 and H3K27me3 levels in prostate cancer cells. EGCG/GTP exposure also reduced MMP‐2/MMP‐9 gelatinolytic activity and abrogated invasion and migration capabilities in these cells. Silencing of EZH2 and class I HDACs strikingly increased the expression of TIMP‐3 independent of DNA methylation. Furthermore, clinical trials performed on patients undergoing prostatectomy consuming 800 mg EGCG (Polyphenon E) up to 6 weeks and grade‐matched controls demonstrate an increase in plasma TIMP‐3 levels. A marked reduction in class I HDACs activity/expression and EZH2 and H3K27me3 levels were noted in GTP‐supplemented prostate tissue. Our findings highlight that TIMP‐3 induction, as a key epigenetic event modulated by green tea in restoring the MMP:TIMP balance suppresses prostate cancer progression.

EGCG Mediated Targeting of Deregulated Signaling Pathways and Non-Coding RNAs in Different Cancers: Focus on JAK/STAT, Wnt/β-Catenin, TGF/SMAD, NOTCH, SHH/GLI, and TRAIL Mediated Signaling Pathways

“…Essentially, green tea polyphenols and EGCG treatment significantly reduced class I histone deacetylases (HDAC) activity/expression in prostate cancer cells. Furthermore, levels of EZH2 and H3K27me3 were also found to be reduced in prostate cancer cells [25]. Data clearly suggested that EGCG efficiently demonstrated multi-layered regulation of HDACs and EZH2.…”

“…There was a considerable reduction in the levels of enhancers of zeste homolog 2 (EZH2) and H3K27me3 repressive marks at the promoter region of TIMP-3. Additionally, there was an evident increase in histone H3K9/18 acetylation [25]. Essentially, green tea polyphenols and EGCG treatment significantly reduced class I histone deacetylases (HDAC) activity/expression in prostate cancer cells.…”

Fluctuations of Histone Chemical Modifications in Breast, Prostate, and Colorectal Cancer: An Implication of Phytochemicals as Defenders of Chromatin Equilibrium

“…As described above, Deb et al analyzed the amount of TIMP3 in plasma samples after polyphenon E treatment in patients in the period between tumor biopsy and radical prostatectomy. HDAC 1 activity, EZH2, and trimethylations in H3K27 were reduced in GTPs supplemented prostate tissue [142]. Similarly, SFN demonstrated significant modulation properties via the regulation of PHMs in the clinical study, in which the level of HDAC activity was evaluated in healthy volunteers.…”

“…Extensive oncological research demonstrated that plant natural compounds may be effective in targeting epigenetic alterations associated with the cancer promotion and progression as well as the primary chemoprevention by affecting the carcinogenesis in early stages during initiation [167]. A great amount of phytochemicals exerted anticancer activities via modulation of PHMs, as was demonstrated mainly in in vitro as well as in vivo preclinical studies focusing on BC, PC, and CRC [14,118,133,141,142,146,157,160,172]. However, the usefulness of phytochemicals within clinical approaches is not sufficiently investigated in this topic.…”

“…On the other hand, levels of H3K9ac and H3K18ac were higher after treatment with GTPs and EGCG. In the clinical trial, tested patients undergoing proctectomy consumed polyphenon E (1,3g), a GTPs formulation primarily consisting of EGCG, as four capsules per day for up to six weeks, which led to positive epigenetic changes (more about the clinical trial below) [142]. Apigenin (API) is a dietary flavonoid with a plethora of benefits for human health.…”