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

Roxana S. Redis; Luz E. Vela; Weiqin Lu; Juliana Ferreira de Oliveira; Cristina Ivan; Cristian Rodriguez-Aguayo; Douglas Adamoski; Barbara Pasculli; Ayumu Taguchi; Yunyun Chen; Agustin F. Fernandez; Luis Valledor; Katrien Van Roosbroeck; Samuel Chang; Maitri Shah; Garrett Kinnebrew; Leng Han; Yaser Atlasi; Lawrence H. Cheung; Gilbert Y. Huang; Paloma Monroig; Marc S. Ramirez; Tina Catela Ivkovic; Long Van; Hui Ling; Roberta Gafà; Sanja Kapitanovic; Giovanni Lanza; James A. Bankson; Peng Huang; Stephen Y. Lai; Robert C. Bast; Michael G. Rosenblum; Milan Radovich; Mircea Ivan; Geoffrey Bartholomeusz; Han Liang; Mario F. Fraga; William R. Widger; Samir Hanash; Ioana Berindan-Neagoe; Gabriel Lopez-Berestein; Andre L.B. Ambrosio; Sandra M. Gomes Dias; George A. Calin

doi:10.1016/j.molcel.2016.01.015

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

Roxana S. Redis, Luz E. Vela, Weiqin Lu, Juliana Ferreira de Oliveira, Cristina Ivan, Cristian Rodriguez-Aguayo, Douglas Adamoski, Barbara Pasculli, Ayumu Taguchi, Yunyun Chen, Agustin F. Fernandez, Luis Valledor, Katrien Van Roosbroeck, Samuel Chang, Maitri Shah, Garrett Kinnebrew, Leng Han, Yaser Atlasi, Lawrence H. Cheung, Gilbert Y. HuangPaloma Monroig, Marc S. Ramirez, Tina Catela Ivkovic, Long Van, Hui Ling, Roberta Gafà, Sanja Kapitanovic, Giovanni Lanza, James A. Bankson, Peng Huang, Stephen Y. Lai, Robert C. Bast, Michael G. Rosenblum, Milan Radovich, Mircea Ivan, Geoffrey Bartholomeusz, Han Liang, Mario F. Fraga, William R. Widger, Samir Hanash, Ioana Berindan-Neagoe, Gabriel Lopez-Berestein, Andre L.B. Ambrosio, Sandra M. Gomes Dias, George A. Calin

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131 Scopus citations

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 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.

Original language	English (US)
Pages (from-to)	520-534
Number of pages	15
Journal	Molecular cell
Volume	61
Issue number	4
DOIs	https://doi.org/10.1016/j.molcel.2016.01.015
State	Published - Feb 18 2016

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Cell Biology

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10.1016/j.molcel.2016.01.015

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Redis, R. S., Vela, L. E., Lu, W., Ferreira de Oliveira, J., Ivan, C., Rodriguez-Aguayo, C., Adamoski, D., Pasculli, B., Taguchi, A., Chen, Y., Fernandez, A. F., Valledor, L., Van Roosbroeck, K., Chang, S., Shah, M., Kinnebrew, G., Han, L., Atlasi, Y., Cheung, L. H., ... Calin, G. A. (2016). Allele-Specific Reprogramming of Cancer Metabolism by the Long Non-coding RNA CCAT2. Molecular cell, 61(4), 520-534. https://doi.org/10.1016/j.molcel.2016.01.015

Redis, RS, Vela, LE, Lu, W, Ferreira de Oliveira, J, Ivan, C, Rodriguez-Aguayo, C, Adamoski, D, Pasculli, B, Taguchi, A, Chen, Y, Fernandez, AF, Valledor, L, Van Roosbroeck, K, Chang, S, Shah, M, Kinnebrew, G, Han, L, Atlasi, Y, Cheung, LH, Huang, GY, Monroig, P, Ramirez, MS, Catela Ivkovic, T, Van, L, Ling, H, Gafà, R, Kapitanovic, S, Lanza, G, Bankson, JA, Huang, P, Lai, SY , Bast, RC, Rosenblum, MG, Radovich, M, Ivan, M, Bartholomeusz, G, Liang, H, Fraga, MF, Widger, WR, Hanash, S, Berindan-Neagoe, I, Lopez-Berestein, G, Ambrosio, ALB, Gomes Dias, SM & Calin, GA 2016, 'Allele-Specific Reprogramming of Cancer Metabolism by the Long Non-coding RNA CCAT2', Molecular cell, vol. 61, no. 4, pp. 520-534. https://doi.org/10.1016/j.molcel.2016.01.015

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title = "Allele-Specific Reprogramming of Cancer Metabolism by the Long Non-coding RNA CCAT2",

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 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.",

author = "Redis, {Roxana S.} and Vela, {Luz E.} and Weiqin Lu and {Ferreira de Oliveira}, Juliana and Cristina Ivan and Cristian Rodriguez-Aguayo and Douglas Adamoski and Barbara Pasculli and Ayumu Taguchi and Yunyun Chen and Fernandez, {Agustin F.} and Luis Valledor and {Van Roosbroeck}, Katrien and Samuel Chang and Maitri Shah and Garrett Kinnebrew and Leng Han and Yaser Atlasi and Cheung, {Lawrence H.} and Huang, {Gilbert Y.} and Paloma Monroig and Ramirez, {Marc S.} and {Catela Ivkovic}, Tina and Long Van and Hui Ling and Roberta Gaf{\`a} and Sanja Kapitanovic and Giovanni Lanza and Bankson, {James A.} and Peng Huang and Lai, {Stephen Y.} and Bast, {Robert C.} and Rosenblum, {Michael G.} and Milan Radovich and Mircea Ivan and Geoffrey Bartholomeusz and Han Liang and Fraga, {Mario F.} and Widger, {William R.} and Samir Hanash and Ioana Berindan-Neagoe and Gabriel Lopez-Berestein and Ambrosio, {Andre L.B.} and {Gomes Dias}, {Sandra M.} and Calin, {George A.}",

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AU - Redis, Roxana S.

AU - Vela, Luz E.

AU - Lu, Weiqin

AU - Ferreira de Oliveira, Juliana

AU - Ivan, Cristina

AU - Rodriguez-Aguayo, Cristian

AU - Adamoski, Douglas

AU - Pasculli, Barbara

AU - Taguchi, Ayumu

AU - Chen, Yunyun

AU - Fernandez, Agustin F.

AU - Valledor, Luis

AU - Van Roosbroeck, Katrien

AU - Chang, Samuel

AU - Shah, Maitri

AU - Kinnebrew, Garrett

AU - Han, Leng

AU - Atlasi, Yaser

AU - Cheung, Lawrence H.

AU - Huang, Gilbert Y.

AU - Monroig, Paloma

AU - Ramirez, Marc S.

AU - Catela Ivkovic, Tina

AU - Van, Long

AU - Ling, Hui

AU - Gafà, Roberta

AU - Kapitanovic, Sanja

AU - Lanza, Giovanni

AU - Bankson, James A.

AU - Huang, Peng

AU - Lai, Stephen Y.

AU - Bast, Robert C.

AU - Rosenblum, Michael G.

AU - Radovich, Milan

AU - Ivan, Mircea

AU - Bartholomeusz, Geoffrey

AU - Liang, Han

AU - Fraga, Mario F.

AU - Widger, William R.

AU - Hanash, Samir

AU - Berindan-Neagoe, Ioana

AU - Lopez-Berestein, Gabriel

AU - Ambrosio, Andre L.B.

AU - Gomes Dias, Sandra M.

AU - Calin, George A.

PY - 2016/2/18

Y1 - 2016/2/18

N2 - 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.

AB - 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.

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

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