Oncogene https://doi.org/10.1038/s41388-018-0469-8 ARTICLE The FOXC1/FBP1 signaling axis promotes colorectal cancer proliferation by enhancing the Warburg effect Qingguo Li 1,2 ● Ping Wei 2,3,4 ● Jitao Wu 5 ● Meng Zhang 2,3 ● Guichao Li 2,6 ● Yaqi Li 1,2 ● Ye Xu 1,2 ● Xinxiang Li 1,2 ● Dacheng Xie 7 ● Sanjun Cai 1,2 ● Keping Xie 7 ● Dawei Li 1,2 Received: 12 October 2017 / Revised: 1 August 2018 / Accepted: 2 August 2018 © Springer Nature Limited 2018 Abstract Aberrant expression of Forkhead box (FOX) transcription factors plays vital roles in carcinogenesis. However, the function of the FOX family member FOXC1 in maintenance of colorectal cancer (CRC) malignancy is unknown. Herein, FOXC1 expression in CRC specimens in The Cancer Genome Atlas (TCGA) cohort was analyzed and validated using immunohistochemistry with a tissue microarray. The effect of FOXC1 expression on proliferation of and glycolysis in CRC cells was assessed by altering its expression in vitro and in vivo. Mechanistic investigation was carried out using cell and molecular biological approaches. Our results showed that FOXC1 expression was higher in CRC specimens than in adjacent benign tissue specimens. Univariate survival analyses of the patients from whom the study specimens were obtained, and validated cohorts indicated that ectopic FOXC1 expression was significantly correlated with shortened survival. Silencing FOXC1 expression in CRC cells inhibited their proliferation and colony formation and decreased their glucose consumption and lactate production. In contrast, FOXC1 overexpression had the opposite effect. Furthermore, increased expression of FOXC1 downregulated that of a key glycolytic enzyme, fructose-1,6-bisphosphatase 1 (FBP1). Mechanistically, FOXC1 bound directly to the promoter regions of the FBP1 gene and negatively regulated its transcriptional activity. Collectively, aberrant FBP1 expression contributed to CRC tumorigenicity, and decreased FBP1 expression coupled with increased FOXC1 expression provided better prognostic information than did FOXC1 expression alone. Therefore, the FOXC1/FBP1 axis induces CRC cell proliferation, reprograms metabolism in CRCs, and constitutes potential prognostic predictors and therapeutic targets for CRC. Introduction Colorectal cancer (CRC) is a major cause of cancer death worldwide [1]. Patients with CRC are stratified using a tumor-node-metastases (TNM) staging system when they were diagnosed. Twenty percent to 25% cases diagnosed with metastatic disease, and metastasis develops in another 25% during follow-up. If CRC is diagnosed at an advanced stage or with metastasis, the 5-year survival is merely 10% These authors contributed equally: Qingguo Li, Ping Wei, Jitao Wu * Keping Xie li_dawei@fudan.edu.cn 1 Department of Colorectal Surgery, Fudan University Shanghai Cancer Center, Shanghai, People’s Republic of China 2 Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, People’s Republic of China 3 Department of Pathology, Fudan University Shanghai Cancer Center, Shanghai, People’s Republic of China 4 Cancer Institute, Fudan University Shanghai Cancer Center, Shanghai, People’s Republic of China 5 Department of Urology, Yantai Yuhuangding Hospital, Yantai, People’s Republic of China 6 Department of Radiation Oncology, Fudan University Shanghai Cancer Center, Shanghai, People’s Republic of China 7 Department of Gastroenterology, Hepatology & Nutrition, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA Electronic supplementary material The online version of this article (https://doi.org/10.1038/s41388-018-0469-8) contains supplementary material, which is available to authorized users. 1234567890();,: 1234567890();,: