Pokemon in tumorigenesis: An essential and harmful player

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The transcriptional repressor Pokemon directly inhibits expression of the tumor suppressor gene ARF and plays a critical role in oncogenesis.

Inhibition of transcriptional repression is known to suppress tumorigenesis, as shown through the use of histone deacetylase (HDAC) inhibitors as a cancer treatment. However, the underlying molecular mechanism for this action has not yet been described. Maeda et al. now show that the transcriptional repressor Pokemon —a member of the HDAC-recruiting POK family of proteins— is both necessary and sufficient for oncogenic transformation, thus explaining the observed correlation between transcriptional derepression and tumor inhibition.

Using mouse embryonic fibroblasts lacking the Pokemon encoding gene Zbtb7 in combination with the over-expression of different oncogenes that normally lead to cellular transformation, Maeda et al. showed that Pokemon is required for the transforming activity of several oncogenes.

Speculating that the essentiality of Pokemon for transformation could be explained by direct Pokemon-mediated repression of a pivotal cellular tumor suppressor, the authors screened for a putative Pokemon-binding DNA-sequence. Using CAST (cyclic amplification and selection of targets) analysis together with electrophoretic mobility-shift assays, they identified such a sequence and compared it to the promoters of key tumor suppressor genes to reveal the promoter as target. The authors went on to show that Pokemon does bind to the p19^Arfpromoter and represses its activity both in vitro and in vivo. Furthermore, they found that p19^Arf and Pokemon protein levels were inversely correlated in primary cells, thus confirming that Pokemon is an important and selective repressor of p19^Arf.

Maeda et al. generated transgenic mice over-expressing Pokemon in both immature T and B cells and found aggressive and fatal tumors. Immunohistochemistry revealed intense signals for Pokemon in these lymphomas, thus clearly defining Pokemon as a new proto-oncogene. Finally, the authors found high levels of Pokeman expression in 25–35% of human follicular and diffuse large B-cell lymphomas and moderate levels in 40–50%, indicating an important role for Pokemon in human cancer.

This study reveals a molecular mechanism whereby a transcriptional repressor controls oncogenic transformation via the repression of a tumor suppressor gene. Remarkably, Pokemon is not only necessary for oncogenic transformation but is also a genuine proto-oncogene, making it a potential target for anti-cancer therapy.

References

Maeda, Takahiro, Hobbs, Robin M., Merghoub, Taha, Guernah, Ilhem, Zelent, Arthur, Cordon-Cardo, Carlos, Teruya-Feldstein, Julie, & Pandolfi, Pier Paolo. Role of the proto-oncogene Pokemon in cellular transformation and ARF repression. Nature 433, 278–285 (20 January 2005); nature03203 | Article | PubMed |