Dataset Information

Genistein depletes telomerase activity through cross-talk between genetic and epigenetic mechanisms.

ABSTRACT: Genistein, a natural isoflavone found in soybean products, has been reported to down-regulate telomerase activity and that this prevents cancer and contributes to the apoptosis of cancer cells. However, the precise molecular mechanism by which genistein represses telomerase is not clear. Here, we show that genistein inhibits the transcription of hTERT (human telomerase reverse transcriptase), the catalytic subunit of the human telomerase enzyme, in breast MCF10AT benign cells and MCF-7 cancer cells in a time- and dose-dependent manner. Three major DNA methyltransferases (DNMT1, 3a and 3b) were also decreased in genistein-treated breast cancer cells suggesting that genistein may repress hTERT by impacting epigenetic pathways. Sequential depletion of the hTERT promoter revealed that the hTERT core promoter region is responsible for the genistein-induced repression of hTERT transcription. Using a newly developed technique of chromatin immunoprecipitation (ChIP)-related bifulfite sequencing analysis, we found an increased binding of E2F-1 to the hTERT promoter is due to the site-specific hypomethylation of the E2F-1 recognition site. In addition, we found that genistein can remodel chromatin structures of the hTERT promoter by increasing trimethyl-H3K9 but decreasing dimethyl-H3K4 in the hTERT promoter. The repression of hTERT was enhanced by combination with genistein and the DNMT inhibitor, 5-aza-2'-deoxycytidine (5-aza-dCyd). These findings collectively show that genistein is working, at least in part, through epigenetic mechanisms of telomerase inhibition in breast benign and cancer cells and may facilitate approaches to breast cancer prevention and treatment using an epigenetic modulator combined with genistein.

SUBMITTER: Li Y

PROVIDER: S-EPMC2995334 | biostudies-literature | 2009 Jul

REPOSITORIES: biostudies-literature

ACCESS DATA

Publications

Genistein depletes telomerase activity through cross-talk between genetic and epigenetic mechanisms.

Li Yuanyuan Y Liu Liang L Andrews Lucy G LG Tollefsbol Trygve O TO

International journal of cancer 20090701 2

Genistein, a natural isoflavone found in soybean products, has been reported to down-regulate telomerase activity and that this prevents cancer and contributes to the apoptosis of cancer cells. However, the precise molecular mechanism by which genistein represses telomerase is not clear. Here, we show that genistein inhibits the transcription of hTERT (human telomerase reverse transcriptase), the catalytic subunit of the human telomerase enzyme, in breast MCF10AT benign cells and MCF-7 cancer ce ...[more]

PMID: 19358274

Similar Datasets

Project description:Tuberculosis is caused by Mycobacterium tuberculosis (Mtb) infection. Mtb is one of the oldest human pathogens, and evolves mechanisms implied in human evolution. The lungs are the first organ exposed to aerosol-transmitted Mtb during gaseous exchange. Therefore, the guards of the immune system in the lungs, such as macrophages (M?s) and dendritic cells (DCs), are the most important defense against Mtb infection. There have been several studies discussing the functions of M?s and DCs during Mtb infection, but the genome-wide pathways and networks are still incomplete. Furthermore, the immune response induced by M?s and DCs varies. Therefore, we analyzed the cross-talk genome-wide genetic-and-epigenetic interspecies networks (GWGEINs) between M?s vs. Mtb and DCs vs. Mtb to determine the varying mechanisms of both the host and pathogen as it relates to M?s and DCs during early Mtb infection. First, we performed database mining to construct candidate cross-talk GWGEIN between human cells and Mtb. Then we constructed dynamic models to characterize the molecular mechanisms, including intraspecies gene/microRNA (miRNA) regulation networks (GRNs), intraspecies protein-protein interaction networks (PPINs), and the interspecies PPIN of the cross-talk GWGEIN. We applied a system identification method and a system order detection scheme to dynamic models to identify the real cross-talk GWGEINs using the microarray data of M?s, DCs and Mtb. After identifying the real cross-talk GWGEINs, the principal network projection (PNP) method was employed to construct host-pathogen core networks (HPCNs) between M?s vs. Mtb and DCs vs. Mtb during infection process. Thus, we investigated the underlying cross-talk mechanisms between the host and the pathogen to determine how the pathogen counteracts host defense mechanisms in M?s and DCs during Mtb H37Rv early infection. Based on our findings, we propose Rv1675c as a potential drug target because of its important defensive role in M?s. Furthermore, the membrane essential proteins v1098c, and Rv1696 (or cytoplasm for Rv0667), in Mtb could also be potential drug targets because of their important roles in Mtb survival in both cell types. We also propose the drugs Lopinavir, TMC207, ATSM, and GTSM as potential therapeutic treatments for Mtb infection since they target the above potential drug targets.

Dataset Information

Genistein depletes telomerase activity through cross-talk between genetic and epigenetic mechanisms.

Publications

Genistein depletes telomerase activity through cross-talk between genetic and epigenetic mechanisms.

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets