Characterization of the Molecular and Ionic Properties of the Histidine-Rich Protein Isolated From Newborn Rat Epidermis

Histidine-rich protein from newborn rat epidermis has been further characterized. Polyacrylamide gel electrophoresis in 8 M urea demonstrated dissociation of the protein, a possible oligomeric series, and one major band with two minor bands of the, pH 5.0 precipitate. Amino acid analysis correlated well with previous analyses (except for lower levels of histidine), while the amino acids of high content increased with purification. Sedimentation coefficients and molecular weights determined by ultracentribfugation of all monomers and the residual tissue in histidine-rich protein were in agreement with estimates from gel filtration chromatography. Lower values were obtained for keratohyalin granule proteins. Isoelectric focusing indicated diisoelectric properties of the protein. A molecular model of deamidation is presented in an attempt to explain this property

The transposon-driven evolutionary origin and basis of histone deacetylase functions and limitations in disease prevention

Histone deacetylases (HDACs) are homologous to prokaryotic enzymes that removed acetyl groups from non-histone proteins before the evolution of eukaryotic histones. Enzymes inherited from prokaryotes or from a common ancestor were adapted for histone deacetylation, while useful deacetylation of non-histone proteins was selectively retained. Histone deacetylation served to prevent transcriptions with pathological consequences, including the expression of viral DNA and the deletion or dysregulation of vital genes by random transposon insertions. Viruses are believed to have evolved from transposons, with transposons providing the earliest impetus of HDAC evolution. Because of the wide range of genes potentially affected by transposon insertions, the range of diseases that can be prevented by HDACs is vast and inclusive. Repressive chromatin modifications that may prevent transcription also include methylation of selective lysine residues of histones H3 and H4 and the methylation of selective DNA cytosines following specific histone lysine methylation. Methylation and acetylation of individual histone residues are mutually exclusive. While transposons were sources of disease to be prevented by HDAC evolution, they were also the source of numerous and valuable coding and regulatory sequences recruited by “molecular domestication.” Those sequences contribute to evolved complex transcription regulation in which components with contradictory effects, such as HDACs and HATs, may be coordinated and complementary. Within complex transcription regulation, however, HDACs remain ineffective as defense against some critical infectious and non-infectious diseases because evolutionary compromises have rendered their activity transient

The Role of Nutraceuticals in Chemoprevention and Chemotherapy and Their Clinical Outcomes

The genesis of cancer is often a slow process and the risk of developing cancer increases with age. Altering a diet that includes consumption of beneficial phytochemicals can influence the balance and availability of dietary chemopreventive agents. In chemopreventive approaches, foods containing chemicals that have anticancer properties can be supplemented in diets to prevent precancerous lesions from occurring. This necessitates further understanding of how phytochemicals can potently maintain healthy cells. Fortunately there is a plethora of plant-based phytochemicals although few of them are well studied in terms of their application as cancer chemopreventive and therapeutic agents. In this analysis we will examine phytochemicals that have strong chemopreventive and therapeutic properties in vitro as well as the design and modification of these bioactive compounds for preclinical and clinical applications. The increasing potential of combinational approaches using more than one bioactive dietary compound in chemoprevention or cancer therapy will also be evaluated. Many novel approaches to cancer prevention are on the horizon, several of which are showing great promise in saving lives in a cost-effective manner

Impact of nutrition on non-coding RNA epigenetics in breast and gynecological cancer

Cancer is the second leading cause of death in females. According to the American Cancer Society, there are 327,660 new cases in breast and gynecological cancers estimated in 2014, placing emphasis on the need for cancer prevention and new cancer treatment strategies. One important approach to cancer prevention involves phytochemicals, biologically active compounds derived from plants. A variety of studies on the impact of dietary compounds found in cruciferous vegetables, green tea, and spices like curry and black pepper have revealed epigenetic changes in female cancers. Thus, an important emerging topic comprises epigenetic changes due to the modulation of noncoding RNA levels. Since it has been shown that non-coding RNAs such as microRNAs and long non-coding RNAs are aberrantly expressed in cancer, and furthermore are linked to distinct cancer phenotypes, understanding the effects of dietary compounds and supplements on the epigenetic modulator non-coding RNA is of great interest. This article reviews the current findings on nutrition-induced changes in breast and gynecological cancers at the non-coding RNA level

Epigenomics of Ovarian Cancer and Its Chemoprevention

Ovarian cancer is a major cause of death among gynecological cancers and its etiology is still unclear. Currently, the two principle obstacles in treating this life threatening disease are lack of effective biomarkers for early detection and drug resistance after initial chemotherapy. Similar to other cancers, the initiation and development of ovarian cancer is characterized by disruption of oncogenes and tumor suppressor genes by both genetic and epigenetic mechanisms. While it is well known that it is challenging to treat ovarian cancer through a genetic strategy due in part to its heterogeneity, the reversibility of epigenetic mechanisms involved in ovarian cancer opens exciting new avenues for treatment. The epigenomics of ovarian cancer has therefore become a rapidly expanding field leading to intense investigation. A review on the current status of the field is thus warranted. In this analysis, we will evaluate the current status of epigenomics of ovarian cancer and will include epigenetic mechanisms involved in ovarian cancer development such as DNA methylation, histone modifications, and non-coding microRNA. Development of biomarkers, the epigenetic basis for drug resistance and improved chemotherapy for ovarian cancer will also be assessed. In addition, the potential use of natural compounds as epigenetic modulators in chemotherapy shows promise in moving to the forefront of ovarian cancer treatment strategies

Bioactive Dietary Supplements Reactivate ER Expression in ER-Negative Breast Cancer Cells by Active Chromatin Modifications

Breast cancer is the most common cancer and the leading cause of cancer death in women. Although tamoxifen therapy is successful for some patients, it does not provide adequate benefit for those who have estrogen receptor (ER)-negative cancers. Therefore, we approached novel treatment strategies by combining two potential bioactive dietary supplements for the reactivation of ERα expression for effective treatment of ERα-negative breast cancer with tamoxifen. Bioactive dietary supplements such as green tea polyphenols (GTPs) and sulforaphane (SFN) inhibit DNA methyltransferases (DNMTs) and histone deacetylases (HDACs), respectively, which are of central importance to cancer prevention. In the present study, we have observed that treatment of ERα-negative breast cancer cells with GTPs and SFN alone or in combination leads to the reactivation of ERα expression. The combination of 20 µg/mL GTPs and 5 µM SFN was found to be the optimal dose of ERα-reactivation at 3 days in MDA-MB-231 cells. The reactivation of ERα expression was consistently correlated with ERα promoter hypomethylation and hyperacetylation. Chromatin immunoprecipitation (ChIP) analysis of the ERα promoter revealed that GTPs and SFN altered the binding of ERα-transcriptional co-repressor complex thereby contributing to ERα-reactivation. In addition, treatment with tamoxifen in combination with GTPs and SFN significantly increased both cell death and inhibition of cellular proliferation in MDA-MB-231 cells in comparison to treatment with tamoxifen alone. Collectively, our findings suggest that a novel combination of bioactive-HDAC inhibitors with bioactive-demethylating agents is a promising strategy for the effective treatment of hormonal refractory breast cancer with available anti-estrogens

Association of Body Composition with Odds of Breast Cancer by Molecular Subtype: Analysis of the Mechanisms for Established and Novel Risk Factors for Breast Cancer in Nigerian Women (MEND) Study

BACKGROUND: The association between obesity and breast cancer (BC) has been extensively studied among US, European and Asian study populations, with often conflicting evidence. However, despite the increasing prevalence of obesity and associated conditions in Africa, the continent with the highest age-standardized BC mortality rate globally, few studies have evaluated this association, and none has examined in relation to molecular subtypes among African women. The current analysis examines the association between body composition, defined by body mass index (BMI), height, and weight, and BC by molecular subtype among African women. METHODS: We estimated odds ratios (ORs) and 95% confidence intervals (95% CI) for the association between measures of body composition and BC and molecular subtypes among 419 histologically confirmed cases of BC and 286 healthy controls from the Mechanisms for Established and Novel Risk Factors for Breast Cancer in Women of Nigerian Descent (MEND) case-control study. RESULTS: Higher BMI (aOR: 0.79; 95% CI: 0.67, 0.95) and weight (aOR: 0.83; 95% CI: 0.69, 0.98) were associated with reduced odds of BC in adjusted models, while height was associated with non-statistically significant increased odds of BC (aOR: 1.07, 95% CI: 0.90, 1.28). In pre/peri-menopausal, but not post-menopausal women, both higher BMI and weight were significantly associated with reduced odds of BC. Further, higher BMI was associated with reduced odds of Luminal A, Luminal B, and HER2-enriched BC among pre/peri-menopausal women, and reduced odds of triple-negative BC among post-menopausal women. CONCLUSIONS: Higher BMI and weight were associated with reduced odds of BC overall and by molecular subtype among West African women. Larger studies of women of African descent are needed to definitively characterize these associations and inform cancer prevention strategies

p16INK4a Suppression by Glucose Restriction Contributes to Human Cellular Lifespan Extension through SIRT1-Mediated Epigenetic and Genetic Mechanisms

Although caloric restriction (CR) has been shown to increase lifespan in various animal models, the mechanisms underlying this phenomenon have not yet been revealed. We developed an in vitro system to mimic CR by reducing glucose concentration in cell growth medium which excludes metabolic factors and allows assessment of the effects of CR at the cellular and molecular level. We monitored cellular proliferation of normal WI-38, IMR-90 and MRC-5 human lung fibroblasts and found that glucose restriction (GR) can inhibit cellular senescence and significantly extend cellular lifespan compared with cells receiving normal glucose (NG) in the culture medium. Moreover, GR decreased expression of p16INK4a (p16), a well-known senescence-related gene, in all of the tested cell lines. Over-expressed p16 resulted in early replicative senescence in glucose-restricted cells suggesting a crucial role of p16 regulation in GR-induced cellular lifespan extension. The decreased expression of p16 was partly due to GR-induced chromatin remodeling through effects on histone acetylation and methylation of the p16 promoter. GR resulted in an increased expression of SIRT1, a NAD-dependent histone deacetylase, which has positive correlation with CR-induced longevity. The elevated SIRT1 was accompanied by enhanced activation of the Akt/p70S6K1 signaling pathway in response to GR. Furthermore, knockdown of SIRT1 abolished GR-induced p16 repression as well as Akt/p70S6K1 activation implying that SIRT1 may affect p16 repression through direct deacetylation effects and indirect regulation of Akt/p70S6K1 signaling. Collectively, these results provide new insights into interactions between epigenetic and genetic mechanisms on CR-induced longevity that may contribute to anti-aging approaches and also provide a general molecular model for studying CR in vitro in mammalian systems