Allele-Specific Reprogramming of Cancer Metabolism by the Long Non-coding RNA CCAT2

Altered energy metabolism is a cancer hallmark as malignant cells tailor their metabolic pathways to meet their energy requirements. Glucose and glutamine are the major nutrients that fuel cellular metabolism, and the pathways utilizing these nutrients are often altered in cancer. Here, we show that the long ncRNA CCAT2, located at the 8q24 amplicon on cancer risk-associated rs6983267 SNP, regulates cancer metabolism in vitro and in vivo in an allele-specific manner by binding the Cleavage Factor I (CFIm) complex with distinct affinities for the two subunits (CFIm25 and CFIm68). The CCAT2 interaction with the CFIm complex fine-tunes the alternative splicing of Glutaminase (GLS) by selecting the poly(A) site in intron 14 of the precursor mRNA. These findings uncover a complex, allele-specific regulatory mechanism of cancer metabolism orchestrated by the two alleles of a long ncRNA. Redis et al. report that the two alleles of the lncRNA, CCAT2, induce distinct metabolic phenotypes. By interacting with the CFIm complex with allele-specific affinities, CCAT2 regulates the alternative splicing of GLS, resulting in the preferential expression of the more aggressive splice isoform