Abstract
The retinoblastoma protein (RB)–E2F1 pathway has a central role in regulating the cell cycle. Several PAX proteins (tissue-specific developmental regulators), including PAX8, interact with the RB protein, and thus regulate the cell cycle directly or indirectly. Here, we report that PAX8 expression is frequent in renal cell carcinoma, bladder, ovarian and thyroid cancer cell lines, and that silencing of PAX8 in cancer cell lines leads to a striking reduction in the expression of E2F1 and its target genes, as well as a proteasome-dependent destabilization of RB protein, with the
RB1
mRNA level remaining unaffected. Cancer cells expressing PAX8 undergo a G
1
/S arrest and eventually senesce following PAX8 silencing. We demonstrate that PAX8 transcriptionally regulates the
E2F1
promoter directly, and
E2F1
transcription is enhanced after RB depletion. RB is recruited to the PAX8-binding site, and is involved in PAX8-mediated
E2F1
transcription in cancer cells. Therefore, our results suggest that, in cancer, frequent and persistent expression of PAX8 is required for cell growth control through transcriptional activation of
E2F1
expression and upregulation of the RB–E2F1 pathway.