长链非编码RNA CCAT2对癌症代谢的等位基因特异性重编程
Allele-Specific Reprogramming of Cancer Metabolism by the Long Non-coding RNA CCAT2.
作者信息
Redis Roxana S, Vela Luz E, Lu Weiqin, Ferreira de Oliveira Juliana, Ivan Cristina, Rodriguez-Aguayo Cristian, Adamoski Douglas, Pasculli Barbara, Taguchi Ayumu, Chen Yunyun, Fernandez Agustin F, Valledor Luis, Van Roosbroeck Katrien, Chang Samuel, Shah Maitri, Kinnebrew Garrett, Han Leng, Atlasi Yaser, Cheung Lawrence H, Huang Gilbert Y, Monroig Paloma, Ramirez Marc S, Catela Ivkovic Tina, Van Long, Ling Hui, Gafà Roberta, Kapitanovic Sanja, Lanza Giovanni, Bankson James A, Huang Peng, Lai Stephen Y, Bast Robert C, Rosenblum Michael G, Radovich Milan, Ivan Mircea, Bartholomeusz Geoffrey, Liang Han, Fraga Mario F, Widger William R, Hanash Samir, Berindan-Neagoe Ioana, Lopez-Berestein Gabriel, Ambrosio Andre L B, Gomes Dias Sandra M, Calin George A
机构信息
Department of Experimental Therapeutics, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA.
Department of Biology & Biochemistry, University of Houston, Houston, TX 77204, USA.
出版信息
Mol Cell. 2016 Feb 18;61(4):520-534. doi: 10.1016/j.molcel.2016.01.015. Epub 2016 Feb 4.
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.
能量代谢改变是一种癌症特征，因为恶性细胞会调整其代谢途径以满足能量需求。葡萄糖和谷氨酰胺是为细胞代谢提供能量的主要营养物质，而利用这些营养物质的途径在癌症中常常发生改变。在此，我们表明，位于癌症风险相关单核苷酸多态性rs6983267所在的8q24扩增子上的长链非编码RNA CCAT2，通过以不同亲和力结合切割因子I（CFIm）复合体的两个亚基（CFIm25和CFIm68），在体外和体内以等位基因特异性方式调节癌症代谢。CCAT2与CFIm复合体的相互作用通过选择前体mRNA内含子14中的聚腺苷酸化位点，微调谷氨酰胺酶（GLS）的可变剪接。这些发现揭示了一种由长链非编码RNA的两个等位基因精心编排的癌症代谢复杂的、等位基因特异性调控机制。
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