FBP1 /miR-24-1/enhancer axis activation blocks renal cell carcinoma progression via Warburg effect

Abstract

Warburg effect is a pivotal hallmark of cancers and appears prevalently in renal cell carcinoma (RCC). FBP1 plays a negative role in Warburg effect as a rate-limiting enzyme in gluconeogenesis, yet its mechanism in RCC remains to be further characterized. Herein, we revealed that FBP1 was downregulated in RCC tissue samples and was related to the poor survival rate of RCC. Strikingly, miR-24-1 whose DNA locus is overlapped with enhancer region chr9:95084940-95087024 was closely linked with the depletion of FBP1 in RCC. Of note, miRNAs like miR-24-1 whose DNA loci are enriched with H3K27ac and H3K4me1 modifications are belonging to nuclear activating miRNAs (NamiRNAs), which surprisingly upregulate target genes in RCC through enhancer beyond the conventional role of repressing target gene expression. Moreover, miR-24-1 reactivated the expression of FBP1 to suppress Warburg effect in RCC cells, and subsequently inhibited proliferation and metastasis of RCC cells. In mechanism, the activating role of miR-24-1 was dependent on enhancer integrity by dual luciferase reporter assay and CRISPR/Cas9 system. Ultimately, animal assay in vivo validated the suppressive function of FBP1 on 786-O and ACHN cells. Collectively, the current study highlighted that activation of FBP1 by enhancer-overlapped miR-24-1 is capable of contributing to Warburg effect repression through which RCC progression is robustly blocked, providing an alternative mechanism for RCC development and as well implying a potential clue for RCC treatment strategy.

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“…1 D); detailed descriptions are listed in Table S4 . In the top 5 down-regulated genes, the regulatory functions of ALDOB [ 37 , 38 ], GPX3 [ 39 ] and FBP1 [ [40] , [41] , [42] ] in RCC have been reported.…”

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“…For example, nuclear-activating RNA (NamiRNA) localizes itself in the nucleus and activates proximal or distal genes by targeting enhancers [29]. Dongen Ju et al found that miR-24-1 inhibited the Warburg effect in cancer cells by targeting the active enhancer in the nucleus to activate FBP1 transcription and slow down aerobic glycolysis, ultimately preventing the development of renal cell carcinoma [30]. Younger et al designed miRNA mimics that specifically bind to target gene promoters and directly inhibit gene transcription [31].…”

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“…Wang et al (32) investigated the mechanisms underlying the role of miR-1236-3p in RCC progression and found that miR-1236-3p directly targets the P21 promoter to regulate its gene expression by using a ChIP assay with biotinylated miR-1236-3p, with the ultimate effect to inhibit its function and leading to the suppression of RCC cell proliferation. The result of a luciferase reporter assay showed that miR-24-1 overexpression enhanced fructose-1,6-bisphosphatase transcription by increasing its enhancer activity to attenuate RCC proliferation and metastasis (33).…”