Post by Hyperspacerebel
Aberrant transcriptional repression through chromatin remodelling and histone deacetylation has been postulated to represent a driving force underlying tumorigenesis because histone deacetylase inhibitors have been found to be effective in cancer treatment. However, the molecular mechanisms by which transcriptional derepression would be linked to tumour suppression are poorly understood. Here we identify the transcriptional repressor
Pokemon (encoded by the Zbtb7 gene) as a critical factor in oncogenesis. Mouse embryonic fibroblasts lacking Zbtb7 are completely refractory to oncogene-mediated cellular transformation. Conversely,
Pokemon overexpression leads to overt oncogenic transformation both in vitro and in vivo in transgenic mice.
Pokemon can specifically repress the transcription of the tumour suppressor gene ARF through direct binding. We find that
Pokemon is aberrantly overexpressed in human cancers and that its expression levels predict biological behaviour and clinical outcome.
Pokemon’s critical role in cellular transformation makes it an attractive target for therapeutic intervention.We have demonstrated that
Pokemon expression levels are critical determinants of the cellular response to oncogenic transformation. We show that the function of this novel member of the POK family of transcriptional repressors is necessary for oncogenic transformation whereas, conversely,
Pokemon can act as a genuine proto-oncogene when overexpressed (Fig. 5f). Importantly, taking advantage of a transgenic mouse model, we demonstrate that
Pokemon can indeed act as a proto-oncogene in vivo. We identify
Pokemon as a potent transcriptional repressor of the p19Arf tumour suppressor gene.
Pokemon is, to our knowledge, the first ARF-specific transcriptional repressor to be identified. Furthermore, p19Arf inactivation rescued the refractoriness to oncogenic transformation of Zbtb72/2 cells. Taken together, these data strongly indicate that, at least in certain cell types, one of the main oncogenic functions of
Pokemon consists of its ability to repress p19Arf expression. Interestingly, real-time RT–PCR analysis of a cohort of DLBCL cases (n=37) revealed that high
Pokemon gene expression is generally correlated with low expression of the p14ARF gene (Supplementary Fig. 6f). Our findings underscore the potential importance of ARF suppression in human tumorigenesis.
We show that Pokemon is expressed at very high levels in a subset of human lymphomas. TMAanalyses in breast, lung, colon, prostate and bladder carcinomas also reveal high levels of Pokemon expression in a subset of these tumours (T.M. and P.P.P., unpublished data). In this respect, it is worth noting that the genomic region where the ZBTB7 gene resides (chromosome 19p13.3) is a hotspot for chromosomal translocations (CGAP;
http://cgap.nci.nih.gov/Chromosomes). We show that
Pokemon expression or its coexpression with BCL6 in lymphoma predicts clinical outcome. This is in keeping with the fact that
Pokemon is required for BCL6 oncogenic activity, and that high expression of potent protooncogenes such as BCL6 and LMO2 also identifies cohorts of patients who respond better to current treatment modalities41,43,45. Cooperative tumorigenesis between these two proto-oncogenes could be exerted through distinct transcriptional programmes or pathways46, but also through co-regulation of common target genes in view of their ability to interact physically. In this respect, it is of interest that BCL6 has recently been reported to repress p53 expression directly47. Our findings provide a further rational for transcription-based therapeutic modalities and identify
Pokemon as an important target for therapy on the basis of its key role in oncogenesis.