Allele-specific reprogramming of cancer metabolism by the long non-coding RNA, CCAT2

Summary Altered energy metabolismis a cancer hallmark as malignant cells tailor their metabolic pathwaysto 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 ncRNACCAT2 , located at the 8q24 ampliconon cancer risk-associated rs6983267 SNP, regulates cancer metabolismin vitro and in vivo in an allele-specific manner by binding the Cleavage FactorI (CFIm) complex with distinct affinities for the two subunits (CFIm25 and CFIm68). The CCAT2 interaction with the CFIm complex fine-tunes the alternative splicingof 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 metabolismorchestrated by the two alleles of a long ncRNA.