Fibrillarin reprograms glucose metabolism by driving the enhancer-mediated transcription of PFKFB4 in liver cancer
Yizhe Liu, Qili Shi, Yanfang Liu, Xinrong Li, Zhen Wang, Shenglin Huang, Zhiao Chen, Xianghuo He
Abstract
DNA- and RNA-binding proteins (DRBPs) are versatile proteins capable of binding to both DNA and RNA molecules. In this study, we identified fibrillarin (FBL) as a key DRBP that is upregulated in liver cancer tissues vs. normal tissues and is correlated with patient prognosis. FBL promotes the proliferation of liver cancer cells both in vitro and in vivo. Mechanistically, FBL interacts with the transcription factor KHSRP, thereby regulating the expression of genes involved in glucose metabolism and leading to the reprogramming of glucose metabolism. Specifically, FBL and KHSRP work together to transcriptionally activate the glycolytic enzyme PFKFB4 by co-occupying enhancer and promoter elements, thereby further promoting liver cancer growth. Collectively, these findings provide compelling evidence highlighting the role of FBL as a transcriptional regulator in liver cancer cells, working in conjunction with KHSRP. The FBL/KHSRP-PFKFB4 regulatory axis holds potential as both a prognostic indicator and a therapeutic target for liver cancer. A novel role of FBL in the transcriptional activation of PFKFB4, leading to glucose metabolism reprogramming in liver cancer. • FBL is upregulated in liver cancer and correlates with patient prognosis and pathological features. • FBL promotes the proliferation of liver cancer cells both in vitro and in vivo. • FBL interacts with KHSRP to regulate the transcription of genes linked to glucose metabolism, leading to its reprogramming. • FBL and KHSRP bind to PFKFB4 enhancers and promoters, activating its transcription, modulating glucose metabolism, and promoting liver cancer growth.