Nuclear PKM2 promotes pre-mRNA processing by binding folded RNA G-quadruplexes

Abstract Nuclear localization of the pyruvate kinase M2 isoform (PKM2) is widely observed in cancer and correlates with its aggressiveness, but its contribution to gene regulation and pathogenesis remains unclear. We find that PKM2 is a non-canonical RNA binding protein that specifically recognizes RNA G-quadruplex (rG4) structures and binds precursor mRNAs (pre-mRNAs) in the nucleus of human cells. Translocation of PKM2 to the nucleus increases expression of transcripts with rG4 elements close to splice sites and promotes RNA biogenesis by competing with repressive rG4 binding proteins, such as HNRNPF. PKM2 target mRNAs are also upregulated in a cancer model undergoing epithelial-to-mesenchymal transition (EMT), and consistently drug-induced exclusion of PKM2 from the nucleus results in downregulated rG4-mRNAs and reduced migration and invasion of triple-negative breast cancer cells. We show a gene-regulatory role for rG4 formation on pre-mRNA and propose that rG4s allow for collective co-transcriptional regulation of related mRNAs by competing RBPs.