Tristetraprolin-mediated hexokinase 2 expression regulation contributes glycolysis in cancer cells

• Published in: Molecular biology of the cell 2019-03, Vol.30 (5), p.mbcE18090606-553
• Main Authors: Kim, Dong Jun, Vo, Mai-Tram, Choi, Seong Hee, Lee, Ji-Heon, Jeong, So Yeon, Hong, Chung Hwan, Kim, Jong Soo, Lee, Unn Hwa, Chung, Hyung-Min, Lee, Byung Ju, Cho, Wha Ja, Park, Jeong Woo
• Format: Article
• Language: English
• ISSN: 1059-1524; 1939-4586
• DOI: 10.1091/mbc.E18-09-0606

Hexokinase 2 (HK2) catalyzes the first step of glycolysis and is upregulated in cancer cells. The mechanism by which HK2 expression is upregulated in cancer cells has not been fully elucidated. Tristetraprolin (TTP) is an AU-rich element (ARE)-binding protein that inhibits the expression of ARE-containing genes by enhancing mRNA degradation. TTP expression is downregulated in cancer cells. We demonstrated that TTP is critical for downregulation of HK2 expression in cancer cells. HK2 mRNA contains an ARE within its 3'-UTR. TTP binds to the HK2 3'-UTR and enhances degradation of HK2 mRNA. TTP overexpression decreased HK2 expression and suppressed the glycolytic capacity of cancer cells measured as glucose uptake and production of glucose-6-phosphate, pyruvate, and lactate. TTP overexpression reduced both the extracellular acidification rate (ECAR) and oxygen consumption rate (OCR) of cancer cells. Ectopic expression of HK2 in cancer cells attenuated the reduction in glycolytic capacity, ECAR and OCR from TTP. Taken together, these findings suggested that TTP acted as a negative regulator of HK2 expression and glucose metabolism in cancer cells.