Oncogenic dysregulation of pre‐mRNA processing by protein kinases: challenges and therapeutic opportunities

Abstract

Alternative splicing and polyadenylation represent two major steps in pre‐mRNA‐processing, which ensure proper gene expression and diversification of human transcriptomes. Deregulation of these processes contributes to oncogenic programmes involved in the onset, progression and evolution of human cancers, which often result in the acquisition of resistance to existing therapies. On the other hand, cancer cells frequently increase their transcriptional rate and develop a transcriptional addiction, which imposes a high stress on the pre‐mRNA‐processing machinery and establishes a therapeutically exploitable vulnerability. A prominent role in fine‐tuning pre‐mRNA‐processing mechanisms is played by three main families of protein kinases: serine arginine protein kinase (SRPK), CDC‐like kinase (CLK) and cyclin‐dependent kinase (CDK). These kinases phosphorylate the RNA polymerase, splicing factors and regulatory proteins involved in cleavage and polyadenylation of the nascent transcripts. The activity of SRPKs, CLKs and CDKs can be altered in cancer cells, and their inhibition was shown to exert anticancer effects. In this review, we describe key findings that have been reported on these topics and discuss challenges and opportunities of developing therapeutic approaches targeting splicing factor kinases.

Abstract

Phosphorylation of RNA polymerase II and regulatory RNA‐binding proteins represents a major modality of pre‐mRNA‐processing regulation. Serine arginine protein kinase (SRPK), CDC‐like kinase (CLK) and cyclin‐dependent kinase (CDK) are the three main families of protein kinases regulating this process. This review reports findings that have highlighted oncogenic alteration of the pre‐mRNA‐processing as a consequence of aberrant regulation of SRPK, CLK and CDK activity and discuss challenges and opportunities of developing therapeutic approaches targeting these kinases.