Abstract 2940: A role for PAX8 in promoting tumor cell type-specific proliferation through positively regulating E2F1 transcription and stabilizing RB protein

• Published in: Cancer research (Chicago, Ill.) Vol. 71; no. 8_Supplement; p. 2940
• Main Authors: Eccles, Mike R., Li, Caiyun G., Nyman, Jennifer E., Braithwaite, Antony W.
• Format: Journal Article
• Language: English
• Published: 15.04.2011
• ISSN: 0008-5472; 1538-7445
• DOI: 10.1158/1538-7445.AM2011-2940

Abstract The PAX proteins are tissue-specific developmental regulators required for fetal development. In most cases, PAX expression is silenced post-natally, although it is maintained in some adult tissues. Several PAX proteins interact with RB, a key protein involved in cell cycle regulation. The phosphorylation of RB leads to the mobilization of the master regulator of cell cycle progression, E2F1. It is presently unknown how the growth and differentiation of a tissue is coordinated in a tissue-specific manner with the regulation of the cell cycle in order to facilitate terminal differentiation, or how this process might be disrupted in cancer. PAX gene dysregulation is observed in many cancer types with PAX8 being frequently expressed in renal cell carcinoma (RCC), bladder, ovarian and thyroid cancer cell lines. We investigated the effect on the RB-E2F1 pathway of knocking-down PAX8 using siRNAs in cell lines corresponding to these four cancer types. Knockdown of PAX8 led to a striking reduction in E2F1 mRNA and protein in cancer cell lines, as well as a reduction in levels of E2F1 target genes, including cyclin A2 (CCNA2) and CDC6, induction of a G1/S cell cycle arrest, the onset of cellular senescence, and a proteosome-dependent destabilization of RB protein, with RB1 mRNA levels remaining unaffected. Using ChIP and luciferase reporter assays we showed that PAX8 binds to and transcriptionally regulates the E2F1 promoter. These data suggest that the expression of PAX8 is associated with transcriptional activation of E2F1 and stabilization of RB protein in cancer cell lines. During development in normal tissues we presume that expression of PAX8 coordinates cell proliferation with tissue-specific growth. In cancer, however, the expression of PAX8 continues unabated, and PAX8 silencing leads cancer cells to undergo cell cycle arrest, and subsequently to become senescent. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 2940. doi:10.1158/1538-7445.AM2011-2940