The products of Pol III genes (
RNA polymerase III-dependent genes), such as tRNAs and
5S rRNA, are elevated in both transformed and
tumor cells suggesting that they play a crucial role in
tumorigenesis. An increase in Brf1 (
TFIIIB-related factor 1), a subunit of
TFIIIB, augments Pol III gene transcription and is sufficient for cell transformation and
tumor formation. We have demonstrated that enhancement of Brf1 and Pol III gene expression is associated with the occurrences of
hepatocellular carcinoma (HCC) in mice. This suggests that Brf1 may be a key molecule during HCC development.
Diethylnitrosamine (DEN), a chemical
carcinogen, has been used to induce HCC in rodents. To determine the role of Brf1 and the epigenetic-regulating events in cell proliferation and transformation, hepatocytes were treated with DEN. The results indicate that DEN increases proliferation and transformation of AML-12 cells. DEN enhanced Brf1 expression and
tRNA(Leu) and
5S rRNA transcription, as well as H3S10ph (phosphorylation of
histone H3 serine 10). Interestingly, DEN-induced Pol III gene transcription and H3S10ph in
tumor cells of liver are significantly higher than in non-
tumor cells. Inhibition of H3S10ph by H3S10A attenuates the induction of Brf1 and Pol III genes. Further analysis indicates that H3S10ph occupies the promoters of Brf1 and Pol III genes to modulate their expression. Blocking H3S10ph represses cell proliferation and transformation. These results demonstrate that DEN induces H3S10ph, which mediate Brf1 expression, including but not limited Brf1-dependent genes, to upregulate Pol III gene transcription, resulting in an increase in cell proliferation and transformation.