SUMMARY 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 alleles of a long ncRNA.

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The translocation of bacteria across the intestinal epithelium of immunocompromised patients can lead to bacteremia and life-threatening sepsis. Extraintestinal pathogenic (ExPEC), so named because this pathotype infects tissues distal to the intestinal tract, is a frequent cause of such infections, is often multidrug resistant, and chronically colonizes a sizable portion of the healthy population. Although several virulence factors and their roles in pathogenesis are well described for ExPEC strains that cause urinary tract infections and meningitis, they have not been linked to translocation through intestinal barriers, a fundamentally distant yet important clinical phenomenon. Using untransformed human intestinal enteroids and transformed Caco-2 cells, we report that ExPEC strain CP9 binds to and invades the intestinal epithelium. ExPEC harboring a deletion of the gene encoding the mannose-binding type 1 pilus tip protein FimH demonstrated reduced binding and invasion compared to strains lacking known virulence factors. Furthermore, in a murine model of chemotherapy-induced translocation, ExPEC lacking colonized at levels comparable to that of the wild type but demonstrated a statistically significant reduction in translocation to the kidneys, spleen, and lungs. Collectively, this study indicates that FimH is important for ExPEC translocation, suggesting that the type 1 pilus is a therapeutic target for the prevention of this process. Our study also highlights the use of human intestinal enteroids in the study of enteric diseases.

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

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