BackgroundH3K27me3 histone marks shape the inhibition of gene transcription. In prostate cancer, the deregulation of H3K27me3 marks might play a role in prostate tumor progression.MethodsWe investigated genome-wide H3K27me3 histone methylation profile using chromatin immunoprecipitation (ChIP) and 2X400K promoter microarrays to identify differentially-enriched regions in biopsy samples from prostate cancer patients. H3K27me3 marks were assessed in 34 prostate tumors: 11 with Gleason score > 7 (GS > 7), 10 with Gleason score ≤ 7 (GS ≤ 7), and 13 morphologically normal prostate samples.ResultsHere, H3K27me3 profiling identified an average of 386 enriched-genes on promoter regions in healthy control group versus 545 genes in GS ≤ 7 and 748 genes in GS > 7 group. We then ran a factorial discriminant analysis (FDA) and compared the enriched genes in prostate-tumor biopsies and normal biopsies using ANOVA to identify significantly differentially-enriched genes. The analysis identified ALG5, EXOSC8, CBX1, GRID2, GRIN3B, ING3, MYO1D, NPHP3-AS1, MSH6, FBXO11, SND1, SPATS2, TENM4 and TRA2A genes. These genes are possibly associated with prostate cancer. Notably, the H3K27me3 histone mark emerged as a novel regulatory mechanism in poor-prognosis prostate cancer.ConclusionsOur findings point to epigenetic mark H3K27me3 as an important event in prostate carcinogenesis and progression. The results reported here provide new molecular insights into the pathogenesis of prostate cancer.

Acetylation is a major modification that is required for gene regulation, genome maintenance and metabolism. A dysfunctional acetylation plays an important role in several diseases, including cancer. A group of enzymes-lysine acetyltransferases are responsible for this modification and act in regulation of transcription as cofactors and by acetylation of histones and other proteins. Tip60, a member of MYST family, is expressed ubiquitously and is the acetyltransferase catalytic subunit of human NuA4 complex. This HAT has a well-characterized involvement in many processes, such as cellular signaling, DNA damage repair, transcriptional and cellular cycle. Aberrant lysine acetyltransferase functions promote or suppress tumorigenesis in different cancers such as colon, breast and prostate tumors. Therefore, Tip60 might be a potential and important therapeutic target in the cancer treatment; new histone acetyl transferase inhibitors were identified and are more selective inhibitors of Tip60.

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Animal models simulating acute human pulpitis are still lacking. The rat incisors present a particular situation where most of their innervation is considered to be unmyelinated and concentrated mainly in the tooth pulp. This study reports on a new model for dental pain induced by inflammatory agents applied to the tooth pulps of incisors. In different groups of rats, artificial crowns were fixed on the lower incisors, after cutting 1-2mm of their distal extremities. A volume of 7-10 microl of solutions of saline, capsaicin (1-10mg/ml) or formalin (2.5% or 5%) was injected in the crown cavity, and the nociceptive behaviour was quantitated following a devised scoring method of four scales. Intradental application of capsaicin produced nociceptive scores in the form of one plateau for 1-2h depending on the concentration used. Similar results were obtained with intradental application of formalin 2.5%. The one plateau of nociceptive scores obtained with formalin contrasts with the biphasic aspect of nociceptive behaviour described with the intradermal formalin test. This discrepancy could be attributed to a difference in the types of afferent fibres involved in each situation. Pretreatment with morphine (2 mg/kg) attenuated, in a naloxone-reversible manner, the nociceptive behaviour observed following intradental application of capsaicin. Pretreatment with meloxicam (a cyclo-oxygenase-2 inhibitor) exerted a less pronounced attenuation of the nociceptive scores when compared with morphine. These results provide evidence for the validity of the described model for the simulation of tooth pulp inflammatory pain in awake animals.

Breast cancer is the most frequently diagnosed malignancy in women worldwide. It is well established that the complexity of carcinogenesis involves profound epigenetic deregulations that contribute to the tumorigenesis process. Deregulated H3 and H4 acetylated histone marks are amongst those alterations. Sirtuin-1 (SIRT1) is a class-III histone deacetylase deeply involved in apoptosis, genomic stability, gene expression regulation and breast tumorigenesis. However, the underlying molecular mechanism by which SIRT1 regulates H3 and H4 acetylated marks, and consequently cancer-related gene expression in breast cancer, remains uncharacterized. In this study, we elucidated SIRT1 epigenetic role and analyzed the link between the latter and histones H3 and H4 epigenetic marks in all 5 molecular subtypes of breast cancer. Using a cohort of 135 human breast tumors and their matched normal tissues, as well as 5 human-derived cell lines, we identified H3k4ac as a new prime target of SIRT1 in breast cancer. We also uncovered an inverse correlation between SIRT1 and the 3 epigenetic marks H3k4ac, H3k9ac and H4k16ac expression patterns. We showed that SIRT1 modulates the acetylation patterns of histones H3 and H4 in breast cancer. Moreover, SIRT1 regulates its H3 acetylated targets in a subtype-specific manner. Furthermore, SIRT1 siRNA-mediated knockdown increases histone acetylation levels at 6 breast cancer-related gene promoters: AR, BRCA1, ERS1, ERS2, EZH2 and EP300. In summary, this report characterizes for the first time the epigenetic behavior of SIRT1 in human breast carcinoma. These novel findings point to a potential use of SIRT1 as an epigenetic therapeutic target in breast cancer.

Histone methylation is essential for gene expression control. Trimethylated lysine 27 of histone 3 (H3K27me3) is controlled by the balance between the activities of JMJD3 demethylase and EZH2 methyltransferase. This epigenetic mark has been shown to be deregulated in prostate cancer, and evidence shows H3K27me3 enrichment on gene promoters in prostate cancer.To study the impact of this enrichment, a transcriptomic analysis with TaqMan Low Density Array (TLDA) of several genes was studied on prostate biopsies divided into three clinical grades: normal (n = 23) and two tumor groups that differed in their aggressiveness (Gleason score ≤ 7 (n = 20) and >7 (n = 19)). ANOVA demonstrated that expression of the gene set was upregulated in tumors and correlated with Gleason score, thus discriminating between the three clinical groups. Six genes involved in key cellular processes stood out: JMJD3, EZH2, MGMT, TRA2A, U2AF1 and RPS6KA2. Chromatin immunoprecipitation demonstrated collocation of EZH2 and JMJD3 on gene promoters that was dependent on disease stage. Gene set expression was also evaluated on prostate cancer cell lines (DU 145, PC-3 and LNCaP) treated with an inhibitor of JMJD3 (GSK-J4) or EZH2 (DZNeP) to study their involvement in gene regulation. Results showed a difference in GSK-J4 sensitivity under PTEN status of cell lines and an opposite gene expression profile according to androgen status of cells.In summary, our data describe the impacts of JMJD3 and EZH2 on a new gene signature involved in prostate cancer that may help identify diagnostic and therapeutic targets in prostate cancer.

Leakage has been addressed as a major contributing factor to inflammatory reactions at the implant–abutment connection, leading to problems such as oral malodor, inflammation, and marginal bone loss. The aim of this study was to investigate in vitro the leakage at implant–abutment interface of OsseoSpeed™ implants connected to original and compatible abutments. A total of 28 OsseoSpeed implants were divided into four groups (n = 7). Each group was connected to four different abutments according to manufacturers’ recommendations: group A (TiDesign™); group B (Natea™); group C (Dual™); and group D (Implanet™) abutments. The inner volume of each implant–abutment combination was calculated and leakage was detected for each group with spectrophotometric analysis at 1 h (D0) and 48 h (D1) of incubation time using Rhodamine B. At 1 h, leakage volume was significantly lower in TiDesign and Dual than in Natea and Implanet (P < 0.001). At 48 h, however, leakage was significantly lower between TiDesign and all other systems (P < 0.005). Compatible abutments do not fit internal connection of OsseoSpeed implants perfectly, which increases the leakage of the final assembly.

The results suggest that short-term simulated mastication affects the extra-light blue inserts but not the more-retentive inserts.