3,3′-Diindolylmethane, but not indole-3-carbinol, inhibits histone deacetylase activity in prostate cancer cells

Abstract

Increased consumption of cruciferous vegetables is associated with a reduced risk of developing prostate cancer. Indole-3-carbinol (I3C) and 3,3′-diindolylmethane (DIM) are phytochemicals derived from cruciferous vegetables that have shown promise in inhibiting prostate cancer in experimental models. Histone deacetylase (HDAC) inhibition is an emerging target for cancer prevention and therapy. We sought to examine the effects of I3C and DIM on HDACs in human prostate cancer cell lines: androgen insensitive PC-3cells and androgen sensitive LNCaP cells. I3C modestly inhibited HDAC activity in LNCaP cells by 25% but no inhibition of HDAC activity was detected in PC-3 cells. In contrast, DIM significantly inhibited HDAC activity in both cell lines by as much as 66%. Decreases in HDAC activity correlated with increased expression of p21, a known target of HDAC inhibitors. DIM treatment caused a significant decrease in the expression of HDAC2 protein in both cancer cell lines but no significant change in the protein levels of HDAC1, HDAC3, HDAC4, HDAC6 or HDAC8 were detected. Taken together, these results show that inhibition of HDAC activity by DIM may contribute to the phytochemicals anti-proliferative effects in the prostate. The ability of DIM to target aberrant epigenetic patterns, in addition to its effects on detoxification of carcinogens, may make it an effective chemopreventive agent by targeting multiple stages of prostate carcinogenesis.

Epigenetic Modifications of Nrf2 by 3,3′-diindolylmethane In Vitro in TRAMP C1 Cell Line and In Vivo TRAMP Prostate Tumors

“…Several naturally occurring anticancer phytochemicals have been shown to possess the ability to prevent cancer via epigenetic modifications (14,15,(39)(40)(41). A previous study showed that DIM possesses the ability to inhibit HDAC activity which correlated with increased expression of p21in both human PC-3 and LNCaP cells (19). However, no study has been reported so far on the potential epigenetic modifications, and the anticancer efficacy of DIM in a transgenic prostate cancer mouse model such as TRAMP mice remains unknown.…”

“…Recently, our laboratory showed that curcumin, a potent anticancer agent against many cancers such as prostate cancer, suppresses DNA methyltransferases (DNMT) expression and modifies the histone deacetylases (HDAC) activity in human prostate LNCaP cells, which might contribute to DNA demethylation in promoter region of Nrf2 gene in TRAMP-C1 cells as well as Neurog1 gene in LNCaP cells (14,15). 3,3′-diindolylmethane (DIM), a compound derived from indole-3-carbinol (I3C), is found abundantly in cruciferous vegetables and its multi-target anticancer and cancer chemopreventive effects have been demonstrated in many in vivo and in vitro cancer models (16)(17)(18)(19). Currently, there are around ten clinical trials being conducted in early stage of prostate, breast, and cervical cancer patients for this compound (www.clinicaltrial.gov).…”

Impact of Epigenetic Dietary Components on Cancer through Histone Modifications

“…In PC-3 and LNCaP cells, DIM markedly reduced HDAC2 activity causing increase expression of p21 [184]. In human colon cancer cells, DIM selectively down-regulated class I HDACs both in vitro and in vivo , which led to inceased expression of p21 and p27 , and induction of DNA damage, resulting in cell cycle arrest in G2 phase and apoptosis, respectively [185].…”

Natural compound-derived epigenetic regulators targeting epigenetic readers, writers and erasers

“…Both DIM and I3C counteract the effects of enterotoxin B (SEB)-induced activation of T cells in mice as inhibitors of class I HDACs, but not class II HDACs [223]. Notably, DIM, but not I3C, specifically decreases HDAC2 activity in LNCaP and PC-3 prostate cancer cells [224]. Recently, the effects of DIM and SFN on genome-wide promoter methylation have been tested in normal prostate epithelial cells and prostate cancer cells, and the results indicated that DIM reversed abnormal methylation in cancer-associated genes [225].…”