Tat-activating regulatory DNA-binding protein regulates glycolysis in hepatocellular carcinoma by regulating the platelet isoform of phosphofructokinase through microRNA 520.

Abstract

UNLABELLED:

Metabolic changes are common features of many cancer cells and are frequently associated with the clinical outcome of patients with various cancers, including hepatocellular carcinoma (HCC). Thus, aberrant metabolic pathways in cancer cells are attractive targets for cancer therapy. However, our understanding of cancer-specific regulatory mechanisms of cell metabolism is still very limited. We found that Tat-activating regulatory DNA-binding protein (TARDBP) is a novel regulator of glycolysis in HCC cells. TARDBP regulates expression of the platelet isoform of phosphofructokinase (PFKP), the rate-limiting enzyme of glycolysis that catalyzes the irreversible conversion of fructose-6-phosphate to fructose-1,6-bisphosphate. Silencing of TARDBP expression in multiple HCC cell lines leads to impaired glucose metabolism and inhibition of in vitro and in vivo growth of HCC cells. Notably, the microRNA 520 (miR-520) family is an intermediate regulator of TARDBP-mediated regulation of glycolysis. Mechanistically, TARDBP suppressed expression of the miR-520 family, which, in turn, inhibited expression of PFKP. We further showed that expression of TARDBP is significantly associated with the overall survival of patients with HCC.

CONCLUSION:

Our study provides new mechanistic insights into the regulation of glycolysis in HCC cells and reveals TARDBP as a potential therapeutic target for HCC.

• Authors: Yun-Yong Park, Sang-Bae Kim, Hee Dong Han, Bo Hwa Sohn, Ji Hoon Kim, Jiyong Liang, Yiling Lu, Cristian Rodriguez-Aguayo, Gabriel Lopez-Berestein, Gordon B Mills, Anil K Sood, Ju-Seog Lee
• Journal: Hepatology (Baltimore, Md.) (Hepatology) Vol. 58 Issue 1 Pg. 182-91 (Jul 2013) ISSN: 1527-3350 [Electronic] United States
• PMID: 23389994 (Publication Type: Journal Article, Research Support, N.I.H., Extramural)
• Copyright: Copyright © 2013 American Association for the Study of Liver Diseases.

Chemical References

• DNA-Binding Proteins
• MIRN520 microRNA, human
• MicroRNAs
• Phosphofructokinase-1, Type C

Topics

• Animals
• Blood Platelets (enzymology)
• Carcinoma, Hepatocellular (metabolism, physiopathology)
• Cell Line, Tumor
• DNA-Binding Proteins (physiology)
• Female
• Glycolysis (drug effects, genetics)
• Humans
• Liver Neoplasms (metabolism, physiopathology)
• Mice
• MicroRNAs (antagonists & inhibitors, physiology)
• Phosphofructokinase-1, Type C (genetics)