SUMMARY Epithelial-mesenchymal transition (EMT) enhances invasiveness and confers tumor cells with cancer stem cell (CSC)-like characteristics. We showed that the Snail-G9a-Dnmt1 complex, which is critical for E-cadherin promoter silencing, is also required for the promoter methylation of fructose-1,6-biphosphatase (FBP1) in basal-like breast cancer (BLBC). Loss of FBP1 induces glycolysis and results in increased glucose uptake, macromolecules biosynthesis, formation of tetrameric PKM2, and maintenance of ATP production under hypoxia. Loss of FBP1 also inhibits oxygen consumption and ROS production by suppressing mitochondrial complex I activity; this metabolic reprogramming results in an increased CSC-like property and tumorigenicity by enhancing the interaction of β-catenin with TCF. Our study indicates that the loss of FBP1 is a critical oncogenic event in EMT and BLBC.

SUMMARY The increased motility and invasiveness of tumor cells are reminiscent of epithelial-mesenchymal transition (EMT) that occurs during embryonic development, wound healing, and metastasis. In this study, we found that Snail is stabilized by the inflammatory cytokine TNFα through the activation of the NF-κB pathway. We demonstrated that NF-κB is required for the induction of COP9 signalosome 2 (CSN2) which, in turn, blocks the ubiquitination and degradation of Snail. Furthermore, we showed that the expression of Snail correlated with the activation of NF-κB in cancer cell lines and metastatic tumor samples. Knockdown of Snail expression inhibited cell migration and invasion induced by inflammatory cytokines and suppressed inflammation-mediated breast cancer metastasis. Our study provides a plausible mechanism for inflammation-induced metastasis.

Tumour necrosis factor-alpha (TNF-a) is an important inflammatory factor that acts as a master switch in establishing an intricate link between inflammation and cancer. A wide variety of evidence has pointed to a critical role of TNF-a in tumour proliferation, migration, invasion and angiogenesis. The function of TNF-a as a key regulator of the tumour microenvironment is well recognised. We will emphasise the contribution of TNF-a and the nuclear factor-kB pathway on tumour cell invasion and metastasis. Understanding the mechanisms underlying inflammation-mediated metastasis will reveal new therapeutic targets for cancer prevention and treatment.