Perspectives on natural product epigenetic modulators in chemical biology and medicine

Abstract

Epigenetic processes are complex regulatory transcriptional pathways that underpin fundamental physiology and are implicated in the aetiology of many diseases. Small molecule modulators of key epigenetic targets will be central in the study of these intricate networks as well as providing highly useful start points for drug discovery efforts. In this review we will give our perspective on the current status of natural product epigenetic modulators, highlighting the limitations, challenges and opportunities for currently identified molecules, as well as potential strategies for novel compound discovery moving forward.

Anticancer Natural Compounds as Epigenetic Modulators of Gene Expression

“…HDACs and histone demethylases, however, remove acetyl and methyl groups, respectively, from histones [361]. HATs have been divided into multiple classes—GNAT (GCN5, PCAF, HAT1, HPA2, HPA3, ATF-2, and NUT1), MYST (MOZ, YBF2, SAS2, and TIP60), EP300/CBP, SRC, CLOCK, RTT109 and TAFII250 (TAFII250) - based on structure, homology, and histone specificity [93, 369]. HATs catalyze histone acetylation, while assisting transcription factors to bind nucleosomal DNA on lysine residues in the N-terminal tails of core histones [93, 369].…”

“…HATs have been divided into multiple classes—GNAT (GCN5, PCAF, HAT1, HPA2, HPA3, ATF-2, and NUT1), MYST (MOZ, YBF2, SAS2, and TIP60), EP300/CBP, SRC, CLOCK, RTT109 and TAFII250 (TAFII250) - based on structure, homology, and histone specificity [93, 369]. HATs catalyze histone acetylation, while assisting transcription factors to bind nucleosomal DNA on lysine residues in the N-terminal tails of core histones [93, 369]. On the contrary, HDACs catalyze deacetylation by cleavage of acetyl groups from the histone molecules, leading to a chromatin compaction and subsequently restricting the binding of transcription factors to DNA, thereby repressing gene expression [359, 369, 370].…”

“…Resveratrol was shown to induce autophagy by activating the NAD-dependent deacetylase, SIRTuin (SIRT)-1, as reviewed in [93]. However, other phenolic compounds found in red wine, including anthocyanins (oenin), stilbenoids (piceatannol), monophenols (caffeic acid, gallic acid) glucosides (delphinidin, kuronamin, peonidin) and flavonoids (catechin, epicatechin, quercetin, myricetin), were found to promote autophagy, and protein deacetylation [403].…”

“…Moreover, FK228 induced the autophagy pathway associated with the Apoptosis Inducible Factor, AIF) translocation from mitochondria to the nucleus [410]. The FDA approved this compound, under a trade name Istodax, for the treatment of cutaneous T-cell lymphoma, as reviewed in [93]. Ursodeoxycholic acid (Ursodiol) from metabolic bycompounds of intestinal bacteria was found to modulate histone acetylation and induce senescence and recently shown acting as a potential anticancer drug for colon cancer prevention [93, 411].…”

Downregulation of LSD1 suppresses the proliferation, tumorigenicity and invasion of papillary thyroid carcinoma K1 cells

“…Since LSD1 shows a strong association with cancer, it may play an important role in the molecular mechanism of thyroid carcinoma. Inhibiters of LSD1, including miRNAs, are used to regulate histone modification (39,40). Therefore, to continue our previous study, the present study analyzed the effects of siRNA targeting LSD1 in papillary thyroid carcinoma K1 cells.…”