SOX9 and GLI1 cooperate in cancer

The transcription factor GLI1 activates the expression of SOX9, and both proteins are known to contribute to the formation of pancreatic ductal adenocarcinomas (PDAs). However, the mechanism by which SOX9 functions downstream of GLI1 has thus far not been well understood. Here (p. 1123), J. Michael Ruppert and colleagues report a positive-feedback interaction between these two factors. Their data show that SOX9 stabilises GLI1 protein levels independently of effects on GLI1 transcription in human PDA cells. In the absence of SOX9, GLI1 is degraded by the proteasome. The degradation of GLI1 is known to be regulated through the E3 ubiquitin ligase SCF^β-TrCP, and the authors now find that GLI1 and SOX9 interact in a mutually exclusive manner with different protein motifs in the β-TrCP subunit of the E3 ligase. In addition, SOX9 disrupts the interaction between the β-TrCP and SKP1 subunits of SCF^β-TrCP. As the authors show, knockdown of SOX9 increases the half-life of β-TrCP and reduces the malignant properties of PDA cells in vitro; the latter effect is reversed by co-suppression of β-TrCP. Both SOX9 and GLI1 are required to maintain PDA cancer stem cells (CSCs), and knockdown of either protein results in very similar expression profiles of CSC markers. SOX9 knockdown also reduces the abundance of other SCF^β-TrCP targets. Taken together, these data provide important insights into the regulation of SOX9 and GLI1 in human cancers.