Laura Faggioli

Trichostatin A, an inhibitor of histone deacetylases, strongly suppresses growth of pancreatic adenocarcinoma cells

In cells with an altered p53 gene, the expression of p21WAF1/CIP1, a potent inhibitor of cyclin‐dependent kinases, can be induced by histone deacetylase (HDAC) inhibitors via a p53‐independent pathway, which may play a critical role in arrest of cell growth. Accordingly, HDAC inhibitors such as trichostatin A (TSA) have potential utility in pancreatic cancer, as most of these tumors possess mutations in p53, which in fact is the main cause of chemoresistance to 5‐fluorouracil. We have analyzed the effect of TSA on the proliferation of nine pancreatic adenocarcinoma cell lines, all containing a mutated p53 gene. TSA strongly inhibited the cellular growth of all these cell lines at submicromolar concentrations. The cellular mechanisms underlying this effect consisted of cell cycle arrest at the G2 phase and apoptotic cell death. The expression of p21WAF1/CIP1 normally induced at the transcriptional level by p53 was also strongly activated by TSA. These findings suggest that inhibitors of HDAC may represent a novel therapeutic strategy for treatment of pancreatic cancer.

Interaction of the nuclear protein CBF1 with the kappaB site of the IL-6 gene promoter.

The nuclear protein CBF1 has been shown to function as an intermediate to target transcription factors,such as the activated Notch receptor,to specific DNA sites. In this paper,we show that CBF1 from cell lines of different origin is able to bind to the[kappa]B site of the IL-6 promoter. By transfection analyses performed in HeLa cells,we demonstrate that overexpressed CBF1 acts as a negative regulator of IL-6 gene transcription and is unable to elicit Notch-dependent activation of this gene. Analyses of protein-DNA interactions indicate that the topology of the complex formed by CBF1 and the target DNA is subtly affected by sequencessurrounding the recognition site. Furthermore,we show that CBF1 induces DNA bending. This finding suggests that CBF1 may influence IL-6 gene transcription by determining a specific conformation of the promoter region.