Transcription factors (TFs) have previously been identified as drivers of cell proliferation in cancer cell lines, but the contribution of specific TFs to tumorigenesis and their mechanism of gene regulation remain unclear. In new research, Giorgio Galli and colleagues identify PAX8 as a candidate oncogene in renal cell carcinoma (RCC) cells and show that the TF this gene encodes activates expression of metabolic genes, including the ferroxidase ceruloplasmin (CP), by binding distal enhancer elements and recruiting histone acetylation activity. “We demonstrate that PAX8 regulates not only cell cycle genes but also metabolic pathways important for RCC,” says Galli.

To identify core TFs that engage with regulatory elements in target genes, Galli and colleagues used a computational approach to map super-enhancers (identified by chromatin immunoprecipitation for H3K27ac) and chromatin accessibility regions (using ATAC sequencing), together with large-scale genetic screens. “Use of these technologies provided an unbiased and comprehensive view of TF dependencies in kidney cancers and led to the identification of PAX8 as a candidate oncogenic factor,” explains Galli.

Further analyses demonstrated that PAX8 regulates the expression of a number of genes linked to cell cycle control and metabolic processes. To further assess the molecular functions of PAX8, the researchers focused on CP, which was the most dysregulated target of PAX8. They found that PAX8 binds to distal enhancer elements, which likely recruits an acetyltransferase-containing complex for gene activation. In cell lines, CP expression correlated with sensitivity to PAX8 silencing. Moreover, analysis of data from The Cancer Genome Atlas revealed an inverse association between expression of CP and survival among RCC cases. “Our findings suggest that understanding the protein complexes engaged by PAX8 in cancerous tissues might reveal the mechanisms that drive tumorigenesis and offer hints as to how PAX8 activity could be modulated for therapeutic purposes,” notes Galli.