Abstract
The roles of long non-coding RNAs in cancer metabolism remain largely unexplored. Here we identify FILNC1 (FoxO-induced long non-coding RNA 1) as an energy stress-induced long non-coding RNA by FoxO transcription factors. FILNC1 deficiency in renal cancer cells alleviates energy stress-induced apoptosis and markedly promotes renal tumor development. We show that FILNC1 deficiency leads to enhanced glucose uptake and lactate production through upregulation of c-Myc. Upon energy stress, FILNC1 interacts with AUF1, a c-Myc mRNA-binding protein, and sequesters AUF1 from binding c-Myc mRNA, leading to downregulation of c-Myc protein. FILNC1 is specifically expressed in kidney, and is downregulated in renal cell carcinoma; also, its low expression correlates with poor clinical outcomes in renal cell carcinoma. Together, our study not only identifies FILNC1 as a negative regulator of renal cancer with potential clinical value, but also reveals a regulatory mechanism by long non-coding RNAs to control energy metabolism and tumor development.
Highlights
The roles of long non-coding RNAs in cancer metabolism remain largely unexplored
Using renal cancer as a model system to study cancer metabolism, we previously showed that activation of FoxO transcription factor, a central regulator of tumor suppression and metabolism[15,16,17,18], in renal cancer cells led to potent cell cycle arrest and apoptosis induction, which is associated with numerous transcriptional alterations of proteincoding genes[19]
Using FoxO(TA)ERT2 stable cell lines, we previously showed that reactivation of FoxO1 or FoxO3 transcription factor by 4OHT treatment (F1 + 4OHT or F3 + 4OHT), compared to vehicle treatment (F1 − 4OHT or F3 − 4OHT), in RCC4 or UMRC2 renal cancer cells induced many transcriptional alterations of proteincoding genes, resulting in cell cycle arrest and apoptosis[19]
Summary
The roles of long non-coding RNAs in cancer metabolism remain largely unexplored. Here we identify FILNC1 (FoxO-induced long non-coding RNA 1) as an energy stress-induced long noncoding RNA by FoxO transcription factors. The regulation of energy sensing and metabolism in cancer development by protein-coding genes has been extensively studied[7], the potential role and mechanism of the more recently identified long non-coding RNAs (lncRNAs) in cancer metabolism remain largely unknown. Current studies on these well-characterized lncRNAs have demonstrated that lncRNAs can function as guides of protein–DNA interactions, scaffolds for protein–protein interactions, decoys to proteins or microRNAs, or enhancers to their neighboring genes[10] Consistent with these diverse biochemical functions of lncRNAs, lncRNAs have been shown to regulate various biological processes, such as cell proliferation, differentiation, survival, and migration, and its dysregulation impacts on different human diseases, such as cancer and metabolic diseases[11]. Renal cell carcinoma (RCC) makes up ~3% of all adult malignancies and ranks among the top ten cancers in the US12, 13
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