Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0282612 (PIN)
 2,291 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Histone variants seem to play a major role in gene expression regulation. In prostate cancer, H2A.Z and its acetylated form are implicated in oncogenes' upregulation. SIRT1, which may act either as tumor suppressor or oncogene, reduces H2A.Z levels in cardiomyocytes, via proteasome-mediated degradation, and this mechanism might be impaired in prostate cancer cells due to sirtuin 1 downregulation. Thus, we aimed to characterize the mechanisms underlying H2A.Z and SIRT1 deregulation in prostate carcinogenesis and how they interact. We found that H2AFZ and SIRT1 were up- and downregulated, respectively, at transcript level in primary prostate cancer and high-grade prostatic intraepithelial neoplasia compared to normal prostatic tissues. Induced SIRT1 overexpression in prostate cancer cell lines resulted in almost complete absence of H2A.Z. Inhibition of mTOR had a modest effect on H2A.Z levels, but proteasome inhibition prevented the marked reduction of H2A.Z due to sirtuin 1 overexpression. Prostate cancer cells exposed to epigenetic modifying drugs trichostatin A, alone or combined with 5-aza-2'-deoxycytidine, increased H2AFZ transcript, although with a concomitant decrease in protein levels. Conversely, SIRT1 transcript and protein levels increased after exposure. ChIP revealed an increase of activation marks within the TSS region for both genes. Remarkably, inhibition of sirtuin 1 with nicotinamide, increased H2A.Z levels, whereas activation of sirtuin 1 by resveratrol led to an abrupt decrease in H2A.Z. Finally, protein-ligation assay showed that exposure to epigenetic modifying drugs fostered the interaction between sirtuin 1 and H2A.Z. We concluded that sirtuin 1 and H2A.Z deregulation in prostate cancer are reciprocally related. Epigenetic mechanisms, mostly histone post-translational modifications, are likely involved and impair sirtuin 1-mediated downregulation of H2A.Z via proteasome-mediated degradation. Epigenetic modifying drugs in conjunction with enzymatic modulators are able to restore the normal functions of sirtuin 1 and might constitute relevant tools for targeted therapy of prostate cancer patients.
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PMID:Regulation of histone H2A.Z expression is mediated by sirtuin 1 in prostate cancer. 2412 49

Nicotinamide N -methyltransferase (NNMT) has been identified to be associated with tumorigenesis and the malignant transformation of numerous types of cancer. The aim of the present study was to explore the expression and prognostic significance of NNMT in prostate cancer (PCa). Immunohistochemical NNMT expression was examined in 26 cases of benign prostate hyperplasia (BPH), 18 cases of high-grade prostatic intraepithelial neoplasia (HGPIN) and 120 cases of PCa. While rarely expressed in BPH (8/26 cases; 30.8%), NNMT was found to be significantly upregulated in HGPIN (15/18 cases; 83.3%) and PCa (77/120 cases; 64.2%). Clinicopathological analysis revealed that NNMT expression was negatively correlated with Gleason score (P<0.001). Furthermore, Kaplan-Meier survival curves revealed that high NNMT expression was associated with prolonged progression-free survival (PFS) and overall survival (OS) times in patients with advanced PCa. Multivariate analysis showed that NNMT was an independent prognostic marker of PFS and OS in patients with advanced PCa. The results of the present study suggested that NNMT may contribute to the development of PCa and may potentially be a favorable prognostic marker for the survival of patients with advanced PCa.
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PMID:Nicotinamide N-methyltransferase is overexpressed in prostate cancer and correlates with prolonged progression-free and overall survival times. 2512 Jun 81