CircPRKAA1 activates a Ku80/Ku70/SREBP-1 axis driving de novo fatty acid synthesis in cancer cells
Description
Many metabolism-related genes undergo alternative splicing to generate circular RNAs although their functions remain poorly understood. Here we report that circPRKAA1, a circRNA derived from the α1 subunit of AMPK, fulfils 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. Secondly, circPRKAA1 selectively binds to the promoters of the ACC1, ACLY, SCD1 and FASN genes to recruit mSREBP-1, upregulating their transcription and increasing fatty acid synthesis to promote cancer growth. Moreover, circPRKAA1 biogenesis is negatively regulated by AMPK activity with lower AMPK activation in hepatocellular carcinoma tissues frequently associated with elevated circPRKAA1 expression. Together, this work identifies circPRKAA1 as an integral element of AMPK-regulated reprogramming of lipid metabolism in cancer cells. This dataset contains the raw data of our study.