circPRKAA1 activates a Ku80/Ku70/SREBP-1 axis driving de novo fatty acid synthesis in cancer cells.
circPRKAA1 activates a Ku80/Ku70/SREBP-1 axis driving de novo fatty acid synthesis in cancer cells.
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DOI：
10.1016/j.celrep.2022.111707
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发表时间：
2022-11
期刊：
影响因子：
8.8
通讯作者：
Qidong Li;H. Yao;Yichun Wang;Yang Wu;R. Thorne;Youming Zhu;Mian Wu;Lianxin Liu
中科院分区：
文献类型：
--
作者：
Qidong Li;H. Yao;Yichun Wang;Yang Wu;R. Thorne;Youming Zhu;Mian Wu;Lianxin Liu
许多代谢相关基因经过选择性剪接产生环状RNA，但其功能仍然知之甚少。在这里，我们报告说，circPRKAA 1，一个环状RNA（circRNA）来自AMP激活的蛋白激酶（AMPK）的α1亚基，履行在维持脂质稳态的基本作用。circPRKAA 1表达通过两种协调功能促进脂肪酸合成和促进脂质储存。首先，circPRKAA 1促进Ku 80/Ku 70异二聚体和成熟形式的固醇调节元件结合蛋白1（mSREBP-1）之间的四聚体复合物，以增强mSREBP-1的稳定性。其次，circPRKAA 1选择性地结合ACC 1、ACLY、SCD 1和FASN基因的启动子以募集mSREBP-1，上调其转录并增加脂肪酸合成以促进癌症生长。circPRKAA 1生物发生受AMPK活性负调控，肝细胞癌组织中较低的AMPK活化通常与circPRKAA 1表达升高相关。这项工作确定circPRKAA 1作为AMPK调节的癌细胞脂质代谢重编程的组成部分。
Many metabolism-related genes undergo alternative splicing to generate circular RNAs, but their functions remain poorly understood. Here we report that circPRKAA1, a circular RNA (circRNA) derived from the α1 subunit of AMP-activated protein kinase (AMPK), fulfills a fundamental role in maintaining lipid homeostasis. circPRKAA1 expression facilitates fatty acid synthesis and promotes lipid storage through two coordinated functions. First, circPRKAA1 promotes a tetrameric complex between the Ku80/Ku70 heterodimer and the mature form of sterol regulatory element-binding protein 1 (mSREBP-1) to enhance the stability of mSREBP-1. Second, circPRKAA1 selectively binds to the promoters of theACC1,ACLY,SCD1, andFASNgenes to recruit mSREBP-1, upregulating their transcription and increasing fatty acid synthesis to promote cancer growth. circPRKAA1 biogenesis is negatively regulated by AMPK activity, with lower AMPK activation in hepatocellular carcinoma tissue frequently associated with elevated circPRKAA1 expression. This work identifies circPRKAA1 as an integral element of AMPK-regulated reprogramming of lipid metabolism in cancer cells.