Nucleoporins are essential for maintaining communication between the nucleus and cytoplasm, and mutations in these proteins have been associated with the development and progression of several types of cancer. However, it remains unclear how the aberrant function of nucleoporins contributes to tumourigenesis.
In this issue, Buttitta and colleagues disrupt the function of nucleoporin (Nup)96 and Nup98, both of which are known to be mutated in cancer, to delineate their role in tumourigenesis. The authors reduced the expression of these nucleoporins in the wing discs of Drosophila using RNA interference and observed disruption of cell cycle exit, along with increased proliferation. Surprisingly, knockdown of Nup98-96 also resulted in smaller wing size, which the authors determined was due to apoptosis induction via overactivation of JNK signalling. The counteracting induction of proliferation and apoptosis via JNK signalling is characteristic of a phenomenon in Drosophila known as apoptosis-induced compensatory proliferation (AIP). The authors revealed that knockdown of Nup98-96 led to the expression of genes associated with AIP, as well as chronic wounding and regeneration. Sustained AIP and wounding phenotypes have been associated with tumourigenesis in colorectal cancer and melanoma, both of which have previously been linked to nucleoporin dysregulation. Furthermore, there was a striking overlap with gene expression signatures of an invasive fly tumour model, and, when apoptosis was inhibited along with the nucleoporins, the Drosophila wings displayed dramatic overgrowth, reminiscent of tumourigenesis.
Interestingly, the authors also observed a decrease in protein synthesis in fly wing discs and mammalian cancer cell lines with reduced Nup98-96. The authors also overexpressed Nup98, and surprisingly detected a similar phenotype to that obtained by knocking down Nup98-96. This suggests that Nup98, and possibly Nup96, act as ‘goldilocks’ genes, as both their up- and downregulation can disrupt normal cell function. Overall, Buttitta and colleagues propose that Nup98-96 disruption leads to defects in protein synthesis, which causes a stress response that activates JNK signalling, resulting in chronic AIP and, ultimately, tumour-like overgrowth when combined with oncogenes that block apoptosis. This study exemplifies the power of Drosophila to delineate cell signalling and mechanisms of disease, and highlights nucleoporins as a potential cancer therapy target.