Abstract: Accumulating evidence indicates that miRNA regulatory circuits play important roles in tumorigenesis. We previously reported that miR-124 is correlated with prognosis of colorectal cancer due to PKM-dependent regulation of glycolysis. However, the mechanism by which miR-124 regulates apoptosis in colorectal cancer remains largely elusive. Here, we show that miR-124 induced significant apoptosis in a panel of colorectal cancer cell lines. The mitochondrial apoptosis pathway was activated by miR-124. Furthermore, the pro-apoptotic role of miR-124 was dependent on the status of PKM1/2 level. PKM1 was required for miR-124-induced apoptosis. Via direct protein-protein interaction, PKM1 promoted HNF4α binding to the promoter region of miR-124 and transcribing miR-124. Moreover, HNF4α or PKM1 had a more dramatic effect on colorectal cancer cell apoptosis in the presence of miR-124. However, inhibition of miR-124 blocked cell apoptosis induced by HNF4α or PKM1. These data indicate that miR-124 not only alters the expression of genes involved in glucose metabolism but also stimulates cancer cell apoptosis. In addition, the positive feedback loop between miR-124 and PKM1/HNF4α plays an important role in colorectal cancer cell apoptosis; it suggests that disrupting this regulatory circuit might be a potential therapeutic tool for colorectal cancer treatment.
Keywords: PKM; HNF4α; miR-124; colorectal cancer
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Sun, Y.; Zhao, X.; Luo, M.; Zhou, Y.; Ren, W.; Wu, K.; Li, X.; Shen, J.; Hu, Y. The Pro-Apoptotic Role of the Regulatory Feedback Loop between miR-124 and PKM1/HNF4α in Colorectal Cancer Cells. Int. J. Mol. Sci. 2014, 15, 4318-4332.
Sun Y, Zhao X, Luo M, Zhou Y, Ren W, Wu K, Li X, Shen J, Hu Y. The Pro-Apoptotic Role of the Regulatory Feedback Loop between miR-124 and PKM1/HNF4α in Colorectal Cancer Cells. International Journal of Molecular Sciences. 2014; 15(3):4318-4332.
Sun, Yan; Zhao, Xiaoping; Luo, Man; Zhou, Yuhong; Ren, Weiying; Wu, Kefen; Li, Xi; Shen, Jiping; Hu, Yu. 2014. "The Pro-Apoptotic Role of the Regulatory Feedback Loop between miR-124 and PKM1/HNF4α in Colorectal Cancer Cells." Int. J. Mol. Sci. 15, no. 3: 4318-4332.