Interconnected genetic and epigenetic events control both the initiation and progression of cancer. Specifically, genetic alterations, such as amplification, and the subsequent over-expression of genes encoding ‘epigenetic modifying enzymes’ can directly lead to histone code changes that may be critical for cancer progression. KDM5A (lysine (K)-specific demethylase 5A, also known as RBP2 and JARID1A) was originally identified as the retinoblastoma-binding protein (RBP) implicated in the regulation of retinoblastoma target genes. Recently, several groups discovered that KDM5A is a member of a set of newly identified histone demethylases that control the chromatin-mediated regulation of gene expression. Specifically, KDM5A can function as a transcriptional repressor through the demethylation of tri- and dimethylated histone H3 at lysine 4 (H3K4) active marks. In this study, we observed a significant amplification and over-expression of the KDM5A gene in various tumors, including breast cancer. We found that breast cancer cells with KDM5A gene amplification had intrinsic drug resistance properties and knocking down KDM5A with shRNAs improved the efficacy of epidermal growth factor receptor (EGFR) inhibitors against these breast cancer cells. Further, up-regulation of KDM5A modified the histone methylation status and altered the expression of a subset of key genes, including the tumor suppressor p21 and the apoptotic effector BAK1, in breast cancer. Our findings suggest that alteration of the KDM5A gene may have a critical role in the pathogenesis of breast cancer. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 2192. doi:1538-7445.AM2012-2192

C-myc is an oncogene that functions both in the stimulation of cell proliferation and in and apoptosis. C-myc elicits its oncogenic activity by causing immortalization, and to a lesser extent the transformation of cells, in addition to several other mechanisms. C-myc may also enhance or reduce the sensitivity of cancer cells to chemotherapy, but how this dual function is controlled is largely unclear. Cyclin D1 (D1) is another oncogene that drives cell cycle progression; it acts as a growth factor sensor to integrate extracellular signals with the cell cycle machinery, though it may also promote apoptosis. C-Myc collaborates with TGFalpha, epidermal growth factor receptor, Ras, PI3K/Akt, and NF-kappaB. in part via coordination in regulation of D1 expression, because D1 is a common downstream effector of these growth pathways. Coordination of c-Myc with D1 or its upstream activators not only accelerates tumor formation, but also may drive tumor progression to a more aggressive phenotype. Because c-Myc may effect immortalization while D1 or its upstream activators elicit transformation, targeting c-myc and D1 may be a good strategy for cancer prevention. Moreover, since D1 imposes chemoresistance on cancer cells, targeting D1 may also be a good strategy for cancer chemotherapy, whereas practicioners should be cautious to downregulate c-myc for chemotherapy, since c-Myc may elicit apoptosis.

No abstract

BackgroundEpidemiological literature regarding the effect of polycystic ovary syndrome (PCOS) as a risk factor for non-alcoholic fatty liver disease (NAFLD) remains inconsistent. Furthermore, it remains debatable whether NAFLD is associated with PCOS as a consequence of shared risk factors or whether PCOS contributes to NAFLD in an independent fashion. Therefore, this meta-analysis was conducted.MethodsThis meta-analysis was conducted in accordance with the guidelines of the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA). Relevant studies published before May 2017 were identified and retrieved from PubMed and Web of Science databases. The data were extracted, and the pooled odds ratios (ORs) and 95% confidence intervals (95% CIs) were calculated.ResultsA total of 17 studies were included into the present analysis. Compared to the control group, the risk of NAFLD in the PCOS group was higher (OR = 2.25, 95% CI = 1.95–2.60). When stratified by BMI and geographic location, the results indicated that the frequency of NAFLD risk was significantly higher in obese subjects (OR = 3.01, 95% CI = 1.88–4.82), non-obese subjects (OR = 2.07, 95% CI = 1.12–3.85), subjects from Europe (OR = 2.00, 95% CI = 1.58–2.52), subjects from the Asia-Pacific Region, (OR = 2.32, 95% CI = 1.89–2.84) and subjects from America (OR = 2.96, 95% CI = 1.93–4.55). In addition, PCOS patients with hyperandrogenism (HA) had a significantly higher risk of NAFLD, compared with controls (OR = 3.31, 95% CI = 2.58–4.24). However, there was no association between PCOS patients without HA and higher risk of NAFLD (OR = 1.46; 95% CI =0.55–3.87). The results of this meta-analysis should be interpreted with caution due to the small number of observational studies and possible confounding factors.ConclusionThe meta-analysis results suggest that PCOS is significantly associated with high risk of NAFLD. Although this association was independent of obesity and geographic region, it might be correlated with HA.