In recent years, a considerable emphasis has been focused on the importance of the naturally available botanicals that can be consumed in an individual's everyday diet and that can also be useful as a chemopreventive or chemotherapeutic agent for certain diseases, including cancers. A wide variety of botanicals, mostly dietary flavonoids or polyphenolic substances, have been reported to possess substantial anti-carcinogenic and antimutagenic activities because of their antioxidant and anti-inflammatory properties. Proanthocyanidins are considered as one of them, and are abundantly available in various parts of the plants, such as fruits, berries, bark and seeds. Their modes of action were evaluated through a number of in vitro and in vivo studies which showed their potential role as anti-carcinogenic agent. We summarize and highlight the latest developments on anti-carcinogenic activities of proanthocyanidins from different sources, specifically from grape seeds, and their molecular targets, such as NF-kappaB, mitogen-activated protein kinases, PI3K/Akt, caspases, cytokines, angiogenesis and cell cycle regulatory proteins and other check points, etc. Although the bioavailability and metabolism data on proanthocyanidins is still largely unavailable, certain reports indicate that at least monomers and smaller oligomeric procyanidins are absorbed in the gut. The modulation of various molecular targets by proanthocyanidins in vitro and in vivo tumor models suggests their importance, contribution and mechanism of action to the prevention of cancers of different organs.

The anti-skin carcinogenic effects of green tea catechins have been studied extensively in vitro and in vivo models but the precise epigenetic molecular mechanisms are still unclear. Accumulating data suggest that dietary phytochemicals may alter cancer risk by modifications of epigenetic processes in the cells. The present study was designed to investigate whether tea catechins, particularly (-)-epigallocatechin-3-gallate (EGCG), would modify epigenetic events to regulate DNA methylation-silenced tumor suppressor genes in skin cancer cells. DNA methylation, histone modifications and tumor suppressor gene expressions were studied in detail using human epidermoid carcinoma A431 cells as an in vitro model after EGCG treatment using cytostaining, western blotting, dot blot analysis, real-time polymerase chain reaction and enzymatic activity assays. Our study shows that EGCG treatment decreased global DNA methylation levels in A431 cells in a dose-dependent manner. EGCG decreased the levels of 5-methylcytosine, DNA methyltransferase (DNMT) activity, messenger RNA (mRNA) and protein levels of DNMT1, DNMT3a and DNMT3b. EGCG decreased histone deacetylase activity and increased levels of acetylated lysine 9 and 14 on histone H3 (H3-Lys 9 and 14) and acetylated lysine 5, 12 and 16 on histone H4 but decreased levels of methylated H3-Lys 9. Additionally, EGCG treatment resulted in re-expression of the mRNA and proteins of silenced tumor suppressor genes, p16INK4a and Cip1/p21. Together, our study provides new insight into the epigenetic mechanism of action of EGCG that may contribute to the chemoprevention of skin cancer and may have important implications for epigenetic therapy.

Epigenetic histone modifications play critical roles in the control of gene transcription. Recently, an increasing number of histone H2A deubiquitinases have been identified and characterized. However, the physiological functions for this entire group of histone H2A deubiquitinases remain unknown. In this study, we revealed that the histone H2A deubiquitinase MYSM1 plays an essential and intrinsic role in early B-cell development. MYSM1 deficiency results in a block in early B-cell commitment and a defect of B-cell progenitors in expression of EBF1 and other B-lymphoid genes. We further demonstrated that MYSM1 de-represses EBF1 transcription in B-cell progenitors by orchestrating histone modifications and transcription factor recruitment to the EBF1 locus. Thus, this study not only uncovers the essential role for MYSM1 in gene transcription during early B cell development, but also underscores the biological significance of reversible epigenetic histone H2A ubiquitination.

Key Points• Mysm1 is required to maintain the quiescence and pool size of HSC, and its deletion severely impairs the survival and function of HSC.• Mysm1 controls HSC homeostasis by regulating Gfi1 expression via modulating histone modifications and transcriptional factors recruitment.Epigenetic histone modifications play critical roles in the control of self-renewal and differentiation of hematopoietic stem cells (HSCs). Mysm1 is a recently identified histone H2A deubiquitinase with essential and intrinsic roles for maintaining functional HSCs. In this study, in addition to confirming this function of Mysm1, by using Mysm1-deficient (Mysm1 2/2 ) mice, we provide more evidence for how Mysm1 controls HSC homeostasis. Mysm1 deletion drives HSCs from quiescence into rapid cycling and increases their apoptotic rate, resulting in an exhaustion of the stem cell pool, which leads to an impaired self-renewal and lineage reconstituting abilities in the Mysm1-deficient mice. Our study identified Gfi1 as one of the candidate genes responsible for the HSC defect in Mysm1-deficient mice. Mechanistic studies revealed that Mysm1 modulates histone modifications and directs the recruitment of key transcriptional factors such as Gata2 and Runx1 to the Gfi1 locus in HSCs. We found that Mysm1 directly associates with the Gfi1 enhancer element and promotes its transcription through Gata2 and Runx1 transactivation. Thus, our study not only elaborates on the initial reports of Mysm1 association with HSC homeostasis but also delineates a possible epigenetic mechanism through which Mysm1 carries out this function in the HSCs. (Blood. 2013; 122(16):2812-2822

Overexposure of the human skin to solar ultraviolet (UV) radiation is the major etiologic factor for development of skin cancers. Here, we report the results of epigenetic modifications in UV-exposed skin and skin tumors in a systematic manner. The skin and tumor samples were collected after chronic exposure of the skin of SKH-1 hairless mice to UVB radiation using a well-established photocarcinogenesis protocol. We found a distinct DNA hypermethylation pattern in the UVB-exposed epidermal skin and UVB-induced skin tumors that was associated with the elevated expression and activity of the DNA methyltransferases (Dnmt) 1, Dnmt3a and Dnmt3b. To explore the role of hypermethylation in skin photocarcinogenesis, we focused on the p16(INK4a) and RASSF1A tumor suppressor genes, which are transcriptionally silenced on methylation. We established that the silencing of these genes in UVB-exposed epidermis and UVB-induced skin tumors is associated with a network of epigenetic modifications, including hypoacetylation of histone H3 and H4 and increased histone deacetylation, as well as recruitment of methyl-binding proteins, including MeCP2 and MBD1, to the methylated CpGs. Higher levels of DNA methylation and DNMT activity in human squamous cell carcinoma specimens than in normal human skin suggest that the data are relevant clinically. Our data indicate for the first time that UVB-induced DNA hypermethylation, enhanced Dnmt activity and histone modifications occur in UVB-exposed skin and UVB-induced skin tumors and suggest that these events are involved in the silencing of tumor suppressor genes and in skin tumor development.