Statins do not directly inhibit the activity of major epigenetic modifying enzymes

The potential anticancer effects of statins—a widely used class of cholesterol loweringdrugs—has generated significant interest, as has the use of epigenetic modifying drugs such asHDAC and DNMT inhibitors. We set out to investigate the effect of statin drugs on epigeneticmodifications in multiple cell lines, including hepatocellular carcinoma, breast carcinoma, leukemicmacrophages, cervical adenocarcinoma, and insulin-secreting cells, as well as liver extracts fromstatin-treated C57B1/6J mice. Cells or cell extracts were treated with statins and with establishedepigenetic modulators, and HDAC, HAT, and DNMT activities were quantified. We also examinedhistone acetylation by immunoblotting. Statins altered neither HDAC nor HAT activity. Accordingly,acetylation of histones H3 and H4 was unchanged with statin treatment. However, statins tended toincrease DNMT activity. These results indicate that direct inhibition of the major classes of epigeneticmodifying enzymes, as previously reported elsewhere, is unlikely to contribute to any anticancereffects of statins. This study concerned global effects on epigenetic enzyme activities and histoneacetylation; whether statins influence epigenetic modifications in certain genomic regions, cannot beruled out and remains to be investigated

Mesothelioma tumor cells modulate dendritic cell lipid content, phenotype and function

Dendritic cells (DCs) play an important role in the generation of anti-cancer immune responses, however there is evidence that DCs in cancer patients are dysfunctional. Lipid accumulation driven by tumor-derived factors has recently been shown to contribute to DC dysfunction in several human cancers, but has not yet been examined in mesothelioma. This study investigated if mesothelioma tumor cells and/or their secreted factors promote increases in DC lipid content and modulate DC function. Human monocyte-derived DCs (MoDCs) were exposed to human mesothelioma tumor cells and tumor-derived factors in the presence or absence of lipoproteins. The data showed that immature MoDCs exposed to mesothelioma cells or factors contained increased lipid levels relative to control DCs. Lipid accumulation was associated with reduced antigen processing ability (measured using a DQ OVA assay), upregulation of the co-stimulatory molecule, CD86, and production of the tolerogenic cytokine, IL-10. Increases in DC lipid content were further enhanced by co-exposure to mesothelioma-derived factors and triglyceride-rich lipoproteins, but not low-density lipoproteins. In vivo studies using a murine mesothelioma model showed that the lipid content of tumor-infiltrating CD4<sup>+</sup>CD8a<sup>-</sup> DCs, CD4<sup>-</sup>CD8a<sup>-</sup> DCs and plasmacytoid DCs increased with tumor progression. Moreover, increasing tumor burden was associated with reduced proliferation of tumor-antigen-specific CD8<sup>+</sup> T cells in tumor-draining lymph nodes. This study shows that mesothelioma promotes DC lipid acquisition, which is associated with altered activation status and reduced capacity to process and present antigens, which may impair the ability of DCs to generate effective anti mesothelioma T cell responses

Mutational analysis in UK patients with a clinical diagnosis of familial hypercholesterolaemia: relationship with plasma lipid traits, heart disease risk and utility in relative tracing

As part of a randomised trial [Genetic Risk Assessment for Familial Hypercholesterolaemia (FH) Trial] of the psychological consequences of DNA-based and non-DNA-based diagnosis of FH, 338 probands with a clinical diagnosis of FH (46% with tendon xanthomas) were recruited. In the DNA-based testing arm (245 probands), using single-strand conformation polymorphism of all exons of the low-density lipoprotein receptor (LDLR) gene, 48 different pathogenic mutations were found in 62 probands (25%), while 7 (2.9%) of the patients had the R3500Q mutation in the apolipoprotein B (APOB) gene. Compared to those with no detected mutation, mean untreated cholesterol levels in those with the APOB mutation were similar, while in those with an LDLR mutation levels were significantly higher (None=9.15 +/- 1.62 vs LDLR=9.13 +/- 1.16 vs APOB=10.26 +/- 2.07 mmol/l p < 0.001, respectively). Thirty seven percent of the detected mutations were in exon 3/4 of LDLR, and this group had significantly higher untreated cholesterol than those with other LDLR mutations (11.71 +/- 2.39 mmol/l vs 9.88 +/- 2.44 mmol/l, p=0.03), and more evidence of coronary disease compared to those with other LDLR or APOB mutations (36 vs 13% p=0.04). Of the probands with a detected mutation, 54 first-degree relatives were identified, of whom 27 (50%) had a mutation. Of these, 18 had untreated cholesterol above the 95th percentile for their age and gender, but there was overlap with levels in the non-carrier relatives such that 12% of subjects would have been incorrectly diagnosed on lipid levels alone. In the non-DNA-based testing arm (82 probands) only 19 of the 74 relatives identified had untreated cholesterol above the 95th percentile for their age and gender, which was significantly lower (p < 0.0005) than the 50% expected for monogenic inheritance. These data confirm the genetic heterogeneity of LDLR mutations in the UK and the deleterious effect of mutations in exon 3 or 4 of LDLR on receptor function, lipids and severity of coronary heart disease. In patients with a clinical diagnosis of FH but no detectable mutation, there is weaker evidence for a monogenic cause compared with relatives of probands with LDLR mutations. This supports the usefulness of DNA testing to confirm diagnosis of FH for the treatment of hyperlipidaemia and for further cascade screening