Transcriptional Regulation of the Warburg Effect in Cancer by SIX1

Aerobic glycolysis (the Warburg effect) facilitates tumor growth, and drugs targeting aerobic glycolysis are being developed. However, how the Warburg effect is directly regulated is largely unknown. Here we show that transcription factor SIX1 directly increases the expression of many glycolytic gen...

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Bibliographic Details
Published in:Cancer cell 2018-03, Vol.33 (3), p.368-385.e7
Main Authors: Li, Ling, Liang, Yingchun, Kang, Lei, Liu, Yang, Gao, Shan, Chen, Siyu, Li, Ying, You, Wenye, Dong, Qian, Hong, Tian, Yan, Zhifeng, Jin, Shuai, Wang, Tao, Zhao, Wei, Mai, Haixing, Huang, Jun, Han, Xiao, Ji, Quanbo, Song, Qi, Yang, Chao, Zhao, Shixin, Xu, Xiaojie, Ye, Qinong
Format: Article
Language:English
Subjects:
aerobic glycolysis
Breast Neoplasms - genetics
Breast Neoplasms - pathology
cancer
Cell Line, Tumor
Cell Proliferation - genetics
Down-Regulation
Gene Expression Regulation, Neoplastic - genetics
Glycolysis - genetics
Homeodomain Proteins - genetics
Humans
microRNA
MicroRNAs - genetics
SIX1
transcription factor
Warburg effect
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Summary:Aerobic glycolysis (the Warburg effect) facilitates tumor growth, and drugs targeting aerobic glycolysis are being developed. However, how the Warburg effect is directly regulated is largely unknown. Here we show that transcription factor SIX1 directly increases the expression of many glycolytic genes, promoting the Warburg effect and tumor growth in vitro and in vivo. SIX1 regulates glycolysis through HBO1 and AIB1 histone acetyltransferases. Cancer-related SIX1 mutation increases its ability to promote aerobic glycolysis and tumor growth. SIX1 glycolytic function is directly repressed by microRNA-548a-3p, which is downregulated, inversely correlates with SIX1, and is a good predictor of prognosis in breast cancer patients. Thus, the microRNA-548a-3p/SIX1 axis strongly links aerobic glycolysis to carcinogenesis and may become a promising cancer therapeutic target. [Display omitted] •SIX1 is a key transcription factor involved in the Warburg effect•SIX1 potentiates the Warburg effect via HBO1 and AIB1•SIX1 glycolytic function is directly repressed by microRNA-548a-3p•The miR-548a-3p/Six1 axis regulates the Warburg effect and tumor growth Li et al. show that transcription factor SIX1 regulates aerobic glycolysis in cancer by binding promoters and recruiting HBO1 and AIB1 to induce the expression of glycolytic genes. SIX1 is negatively regulated by miR-548a-3p, and modulation of components of this pathway affects tumor metabolism and growth.
ISSN:1535-6108
1878-3686
DOI:10.1016/j.ccell.2018.01.010