Oncogenic Signaling in Kidney Cancer Requires Renal Lineage Factor PAX8

Somatic mutations in cancer driver genes generally occur in a tissue-specific manner, suggesting that transcriptional networks required for normal tissue function may also be necessary for oncogenic processes. It remains unknown, however, if interactions between genetic alterations and lineage-specific factors are required to establish cancer type–specific oncogenic programs. Patel and colleagues, using loss-of-function CRISPR screens, identified the dependence of clear-cell renal cell carcinoma (ccRCC) on the renal transcription factors paired box 8 (PAX8) and HNF1B, which when inhibited were found to reduce chromatin accessibility. Parallel analyses also revealed a colocalization of PAX8 and hypoxia-inducible factor 2α (HIF2A) on chromatin more frequently than what would occur by chance, suggesting the interaction of these two proteins at the chromatin level. PAX8 depletion, but not depletion of HNF1B, downregulated the hypoxia gene signature, and investigation into gene regulatory elements that mediate HIF2A-driven ccRCC tumor formation revealed the strongest hit to be an enhancer region within chromosome 11 (E11:69419). Localization of both HIF2A and PAX8 at this loci drives the expression of oncogenic CCND1 (Cyclin D1), a positive regulator of the cell cycle. Moreover, a germline variant at 11q13.3 common in ccRCC, rs7948643, falls specifically within the PAX8 binding motif that is critical for E11:69419 activity, and PAX8 demonstrated a much higher binding affinity for the rs7948643 risk allele, which in turn yields the enhanced activation of oncogenic Cyclin D1. Additionally, it was shown that PAX8 inhibition decreases ccRCC proliferation, which does not occur upon HIF2A inhibition, suggesting a HIF2A-independent oncogenic function of PAX8. Specifically, PAX8 exhibited positive regulation of HNF1B expression, with both PAX8 and HNF1B driving protumorigenic MYC expression. Furthermore, a CRISPRi screen identified two distal MYC enhancers activated by HNF1B in both normal and malignant renal cells. In summary, this study reveals that the renal transcription factor PAX8 is required for the downstream oncogenic signaling of ccRCC driver mutations, supporting that lineage-specific transcription factor activity can mediate both oncogenic signaling and tissue-specific cancer risk associated with specific genetic variants.

Patel SA, Hirosue S, Rodrigues P, Vojtasova E, Richarson EK, Ge J, et al. The renal lineage factor PAX8 controls oncogenic signalling in kidney cancer. Nature 2022;606:999–1006.

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