title: The pro-apoptotic role of the regulatory feedback loop between miR-124 and PKM1/HNF4α in colorectal cancer cells.
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.
authors.affiliation: Department of Geriatrics, Zhongshan Hospital, Fudan University, 180 Fenglin Road, Shanghai 200032, China. sunyansy00@163.com.
authors.forename: Yan
authors.initials: Y
authors.lastname: Sun
authors.affiliation: Department of Nuclear Medicine, Ren Ji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai 200127, China. xiaopingzhaoxp@gmail.com.
authors.forename: Xiaoping
authors.initials: X
authors.lastname: Zhao
authors.affiliation: Department of Geriatrics, Zhongshan Hospital, Fudan University, 180 Fenglin Road, Shanghai 200032, China. luo.man@zs-hospital.sh.cn.
authors.forename: Man
authors.initials: M
authors.lastname: Luo
authors.affiliation: Department of Oncology, Zhongshan Hospital, Fudan University, Shanghai 200032, China. zhou.yuhong@zs-hospital.sh.cn.
authors.forename: Yuhong
authors.initials: Y
authors.lastname: Zhou
authors.affiliation: Department of Geriatrics, Zhongshan Hospital, Fudan University, 180 Fenglin Road, Shanghai 200032, China. ren.weiying@zs-hospital.sh.cn.
authors.forename: Weiying
authors.initials: W
authors.lastname: Ren
authors.affiliation: Department of Geriatrics, Zhongshan Hospital, Fudan University, 180 Fenglin Road, Shanghai 200032, China. wu.kefen@zs-hospital.sh.cn.
authors.forename: Kefen
authors.initials: K
authors.lastname: Wu
authors.affiliation: Department of Geriatrics, Zhongshan Hospital, Fudan University, 180 Fenglin Road, Shanghai 200032, China. li.xi@zs-hospital.sh.cn.
authors.forename: Xi
authors.initials: X
authors.lastname: Li
authors.affiliation: Department of Geriatrics, Zhongshan Hospital, Fudan University, 180 Fenglin Road, Shanghai 200032, China. shen.jiping@zs-hospital.sh.cn.
authors.forename: Jiping
authors.initials: J
authors.lastname: Shen
authors.affiliation: Department of Geriatrics, Zhongshan Hospital, Fudan University, 180 Fenglin Road, Shanghai 200032, China. hu.yu@zs-hospital.sh.cn.
authors.forename: Yu
authors.initials: Y
authors.lastname: Hu
mesh_terms: D017209:Apoptosis / Q000235:genetics*; D015153:Blotting, Western; D045744:Cell Line, Tumor; D015179:Colorectal Neoplasms / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D025461:Feedback, Physiological; D015972:Gene Expression Regulation, Neoplastic; D055785:Gene Knockdown Techniques; D045325:HCT116 Cells; D019073:HT29 Cells; D051557:Hepatocyte Nuclear Factor 4 / Q000235:genetics* / Q000378:metabolism; D006801:Humans; D035683:MicroRNAs / Q000235:genetics*; D011485:Protein Binding; D011770:Pyruvate Kinase / Q000235:genetics* / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction
chemical_list: C496592:HNF4A protein, human; D051557:Hepatocyte Nuclear Factor 4; C509207:MIRN124 microRNA, human; D035683:MicroRNAs; D011770:Pyruvate Kinase