Cancer cells hijack RNA processing to rewrite the message

Abstract

Typically, cancer is thought to arise due to DNA mutations, dysregulated transcription and/or aberrant signalling. Recently, it has become clear that dysregulated mRNA processing, mRNA export and translation also contribute to malignancy. RNA processing events result in major modifications to the physical nature of mRNAs such as the addition of the methyl-7-guanosine cap, the removal of introns and the addition of polyA tails. mRNA processing is a critical determinant for the protein-coding capacity of mRNAs since these physical changes impact the efficiency by which a given transcript can be exported to the cytoplasm and translated into protein. While many of these mRNA metabolism steps were considered constitutive housekeeping activities, they are now known to be highly regulated with combinatorial and multiplicative impacts i.e. one event will influence the capacity to undergo others. Furthermore, alternative splicing and/or cleavage and polyadenylation can produce transcripts with alternative messages and new functionalities. The coordinated processing of groups of functionally related RNAs can potently re-wire signalling pathways, modulate survival pathways and even re-structure the cell. As postulated by the RNA regulon model, combinatorial regulation of these groups is achieved by the presence of shared cis-acting elements (known as USER codes) which recruit machinery for processing, export or translation. In all, dysregulated RNA metabolism in cancer gives rise to an altered proteome that in turn elicits biological responses related to malignancy. Studies of these events in cancer revealed new mechanisms underpinning malignancies and unearthed novel therapeutic opportunities. In all, cancer cells coopt RNA processing, export and translation to support their oncogenic activity.