PerspectiveCancer Metabolism

Transcriptional control of kidney cancer

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Science  20 Jul 2018:
Vol. 361, Issue 6399, pp. 226-227
DOI: 10.1126/science.aau4385

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Clear cell renal cell carcinoma (ccRCC) is a subtype of kidney cancer characterized by inactivation of the von Hippel-Lindau (VHL) gene in ∼90% of patients. VHL is the substrate recognition component of an E3 ubiqutin ligase complex that targets prolyl-hydroxylated proteins for proteasomal degradation (1). The canonical targets of VHL are the α subunits of hypoxia-inducible factors (HIFs), which are oxygen-labile transcription factors that become constitutively stabilized early in ccRCC development and consequently direct transcriptional programs that promote angiogenesis and rewiring of intracellular metabolism (24). Identifying VHL substrates other than HIFαs that escape degradation and contribute to tumorigenesis could represent a new therapeutic approach for ccRCC. On page 290 of this issue, Zhang et al. (5) demonstrate that the transcription factor zinc fingers and homeoboxes 2 (ZHX2) is a previously unidentified VHL target that promotes ccRCC tumorigenesis through regulation of nuclear factor κB (NF-κB) signaling, potentially identifying targets to treat ccRCC.