TARDBP strongly represses expression of the miR-520 family as evidenced by a significant increase in their intracellular levels upon TARDBP depletion. This notion was strengthen by a ChIP assay demonstrating that TARDBP directly bound to GT-rich regions in the miR-520b BI 6727 in vitro promoter. In addition to regulation of miR-520s at the transcriptional level, TARDBP may regulate miR-520s post-transcriptionally because the involvement of TARDBP in miRNA processing has been observed in other
systems.23, 24 Our data are in good agreement with previous studies demonstrating repression of the spermatid-specific gene, SP-10, expression by TARDBP.22, 32 Thus, our study rediscovered a previously recognized molecular function of TARDBP and updated molecular mechanisms and biological roles of TARDBP, especially in cellular metabolism with the use of miRNAs as intermediary regulators. There is growing evidence supporting that miRNAs play important roles in regulation of cellular metabolism.33, 34 Recent studies revealed that miRNAs, such as miR-124, miR-137, miR-340, miR-143, and miR-155, regulate
glycolysis by directly targeting Selleck AZD6738 the 3′ UTR region of HK2 and PKM2.35-37 With prediction analysis based on sequence, we discovered that miR-520a/b/e are major regulators of glycolysis by directly targeting the 3′ UTR of medchemexpress PFKP mRNA. We further demonstrated that TARDBP-mediated suppression of miR-520a/b/e is important for the growth and survival of HCC cells. Importantly, analyses of gene-expression patterns from multiple cancer lineages provide evidences supporting our findings related to molecular functions and mechanisms of TARDBP-mediated PFKP regulation. Expression of TARDBP is significantly higher in tumors than normal tissues. We also have found an inverse correlation of expression patterns
among TARDBP, PFKP, and miR-520s. Expression of TARDBP and PFKP is significantly high in the vast majority of cancer cell lines, whereas expression of miR-520s is very low (Supporting Fig. 4A). This is in good agreement with mechanism postulating that TARDBP suppresses the expression of miR-520s that directly inhibit PFKP to maintain increased glycolysis in cancer cells (Fig. 7E). In conclusion, we found that novel roles of TARDBP are linked to glycolysis by PFKP in HCC. Deregulation of cellular metabolism is one of the hallmarks of cancer cells,38 and altered components of the metabolic pathway represent attractive therapeutic targets.13, 39 Thus, the identification of the TARDBP/miR-520/PFKP axis regulating glycolysis and ATP production elicits a potential new approach to target the tumor-specific metabolic pathway. Additional Supporting Information may be found in the online version of this article.
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