The NPC and Cancers: An Emerging Drug Target
A specific subset of Nups has been linked to human cancers. The most strongly linked are TPR, Nup62, and the cytoplasmic constituents Nup88, Nup98, Nup214, and Nup358/RanBP2. These Nups are implicated in a wide variety of cancers via three mutational routes, namely: chromosomal translocations; single point mutations; and changes in Nup expression levels. The most prevalent types of NPC-related oncogenic mutations are chromosomal translocations that fuse portions of a Nup gene with another gene, generating chimeric fusions with novel functions. Rather than fusions, many tumors instead show greatly increased expression levels of Nup62 and Nup88. The fact that these various oncogenic states have Nup defects in common, despite different underlying causes (fusion vs overexpression) underscores how alteration of NPC function is a key step towards oncogenesis.
The mechanisms by which Nup overexpression or Nup fusion mutations lead to cancer are mostly unknown. Indeed, even the localizations of many of the fusion proteins have not been determined, although at least some may localize to the NPC. Nevertheless, either by direct association with the NPC or by mislocalization of critical components, there is strong evidence that these Nup alterations misregulate nucleocytoplasmic transport and communication, which may aberrantly affect gene transcription and signaling pathways. Many viruses also target the NPC by altering either the structure, copy number, or phosphorylation state of specific Nups. Significantly, the Nups they target are the same ones as are associated with cancers. As viruses have been termed “nature’s cell biologists,” it is likely that they are exploiting some of the same weaknesses as the oncogenic defects to alter cell behaviour and growth for their own gain, further bolstering the idea that alterations of specific Nups underlie the mechanisms of disease.