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.

Abstract Altered energy metabolism is a cancer hallmark as malignant cells tailor their metabolic pathways to meet their energy requirements. Glucose and glutamine are the two major nutrients that fuel cellular metabolism and the pathways utilizing these nutrients are often altered in cancer. In this study we show that the long non-codingRNA CCAT2, located at 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, complementary to the risk for colon cancer. The newly formed RNA:protein complex, CCAT2:CFIm, regulates the alternative splicing of glutaminase 1 (GLS1) by selecting the poly(A) site in intron 14 of the precursor mRNA. This results in the preferential expression of the GAC, the more catalytically active GLS1 isoform. Our findings, supported by data in human colorectal cancer samples from multiple cohorts, including TCGA dataset, and multiple animal models, uncover complex mechanisms of cancer metabolism regulation controlled by a long non-codingRNA. Citation Format: Roxana S. Redis, Cristina Ivan, Luz Vela, Weiqin Lu, Cristian Rodriguez-Aguayo, Andre LB Ambrosio, Sandra M. Gomes Dias, Ioana Berindan-Neagoe, George A. Calin. Allele-specific modulation of cancer metabolism by a long noncoding RNA. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 2871. doi:10.1158/1538-7445.AM2015-2871