No abstract

The hepatitis B virus (HBV) transactivator protein HBx is enigmatic in that it stimulates a striking variety of promoters which do not share a common cis-regulatory element. As it does not bind to DNA, it has been speculated that HBx acts indirectly through cellular pathways. Under certain conditions HBx can have an oncogenic potential, which may be relevant for HBV-associated liver carcinogenesis, but until now the mechanism for transactivation and cell transformation by HBx was unclear. We report here that HBx uses a complex signal transduction pathway for transactivation. An increase in the endogenous protein kinase C (PKC) activator sn-1,2-diacylglycerol and the subsequent activation of PKC give rise to activation of the transcription factor AP-1 (Jun-Fos). As a result, HBx transactivates through binding sites for AP-1 and other PKC-dependent transcription factors (AP-2, NF-kappa B), thereby explaining the as-yet incomprehensible variety of HBx-inducible genes. As the PKC signal cascade also mediates cell transformation by tumour-promoting agents, the mechanism presented here might account for the oncogenic potential of HBx.

Hepatitis B virus (HBV) is regarded as the main aetiologic factor in the development of human hepatocellular carcinoma (HCC), one of the most frequent fatal malignancies worldwide. Detection of integrated HBV sequences in the cellular DNA of almost all HCCs studied, and the recent finding that the integrated HBV open reading frame (orf) X encodes a transactivating activity, supports the notion that integrated HBV DNA could contribute to liver carcinogenesis by activation of cellular genes in trans. But not all HCCs seem to harbour a functional orf X. We report here that 3'-truncated preS2/S sequences in integrated HBV DNA of liver cell carcinomas encode a so far unidentified transcriptional trans-activation activity. This activity is also produced by an artificially 3'-truncated preS2/S gene of the wild-type HBV genome. Besides the simian virus 40 promoter of the reporter plasmid pSV2CAT, the promoter of the human c-myc oncogene can also be activated. These results, taken together with the fact that preS/S is the only HBV gene found to be integrated in almost every HBV-related HCC analysed so far, indicate that trans-activation by integrated preS2/S sequences is a possible mechanism for HBV-associated oncogenesis.

No abstract

Aberrant epigenetic modifications are described in an increasing number of pathological conditions, including neurodegenerative diseases, cardiovascular diseases, diabetes mellitus type 2, obesity and cancer. The general reversibility of epigenetic changes makes them an attractive and promising target e.g. in the treatment of cancer. Thus, a growing number of epigenetically active compounds are currently tested in clinical trials for their therapeutic potential. Interestingly, many phytochemicals present in plant foods, particularly flavonoids, are suggested to be able to alter epigenetic cellular mechanisms. Flavonoids are natural phenol compounds that form a large group of secondary plant metabolites with interesting biological activities. They can be categorized into six major subclasses, which display diverse properties affecting the two best characterized epigenetic mechanisms: modulation of the DNA methylation status and histone acetylation. High dietary flavonoid intake has strongly been suggested to reduce the risk of numerous cancer entities in a large body of epidemiological studies. Established health-promoting effects of diets rich in fruit and vegetables are faced by efforts to use purified flavonoids as supplements or pharmaceuticals, whereupon data on the latter applications remain controversial. The purpose of this review is to give an overview of current research on flavonoids to further elucidate their potential in cancer prevention and therapy, thereby focusing on their distinct epigenetic activities.