Down-regulation of FBP1 by ZEB1-mediated repression confers to growth and invasion in lung cancer cells

Abstract

Lung cancer is the most common type of malignant tumor, but the molecular mechanisms for lung cancer progression remains to be elusive. Here, we demonstrated that FBP1 (Fructose-1, 6-bisphosphatase) was frequently down-regulated in lung cancer tissues and cells, and FBP1 down-regulation was associated with poor prognosis in lung cancer patients. Restored FBP1 expression inhibited glucose uptake and lactate production, but induced oxygen consumption. Restored FBP1 expression also inhibited lung cancer cells proliferation and invasion under hypoxia in vitro, and inhibited lung cancer growth in vivo. Moreover, we confirmed DNA methylation in the promoter contributed to the decrease of FBP1 expression in lung cancer cells. We identified Zinc finger E-box-binding homeobox 1 (ZEB1) bond to FBP1 promoter to enhance DNA methylation in lung cancer cells. Our findings indicate that the down-regulation of FBP1 is a critical oncogenic event in lung cancer progression.

Fructose-1,6-Bisphosphatase 2 Inhibits Sarcoma Progression by Restraining Mitochondrial Biogenesis

“…Transfer a phosphate group from PEP to ADP to yield pyruvate and ATP Acts as a binding partner of Oct-4 and enhances its transcriptional activity (Gao et al, 2012;Hosios et al, 2015;Jiang et al, 2014a;2014b;Lee et al, 2008;Li et al, 2015;Luo et al, 2011;Wang et al, 2014;Yang et al, 2012a;2012b) Interacts (Castonguay et al, 2014;Popanda et al, 1998;Zheng et al, 2003 (Lee et al, 2009;McEwen et al, 1963) oxaloacetate in the TCA cycle facilitating its phosphorylation and acetylation Pyruvate dehydrogenas e complex (PDC) Convert pyruvate to acetyl-CoA Produces acetyl-CoA in the nucleus and increases histone acetylation (Cai et al, 2011;Kim et al, 2006;Sutendra et al, 2014) Promotes cell-cycle progression by increasing acetylation of histones important for G1/S transition and activating S-phase regulator expression (P-Rb, E2F, cyclin A, and Cdk2) ATP-citrate lyase (ACLY) Convert citrate to oxaloacetate and acetyl-CoA Produces acetyl-CoA and increases histone acetylation (Lee et al, 2014;Sivanand et al, 2017;Wellen et al, 2009) Upon DNA damage, nuclear ACLY promotes homologous recombination Acetyl-CoA synthetase short-chain family member 2 (ACSS2) Catalyze acetate to acetyl-CoA Forms a complex with TFEB and increases lysosomal and autophagy gene expression by local histone acetylation (Cheng et al, 2015;Li et al, 2017a;2017b;Zhao et al, 2016) Provides (HSMM, Lonza, CC-2580) were culture in SkBM-2 Basal Medium (Lonza, CC-3246), supplemented with SkGM-2 SingleQuots containing GA-1000, human Epidermal Growth Factor, Dexamethasone and L-glutamine (Lonza, CC-3244). Differentiation should be initiated when the plated myoblasts reach 80-90% confluence and differentiation medium (DMEM with 2% horse serum) was added to the plates and changed every 2-3 days.…”

“…Specifically, in breast cancer cells, histone methyltransferase G9a and DNA methyltransferase DNMT1 are recruited to the FBP1 promoter by Snail, a critical factor in epithelial-to-mesenchymal transitions (EMTs), resulting in increased H3K9me2 and DNA methylation (Dong et al, 2013). Similarly, in lung cancer cells, zinc finger Ebox-binding homeobox 1 (ZEB1) increases DNA methylation by binding to FBP1's promoter (Zhang et al, 2016). In addition, pharmacological inhibition of histone demethylase LSD1 by tranylcypromine remarkably upregulated FBP1 expression (Pan et al, 2013).…”

Inhibiting histone deacetylases suppresses glucose metabolism and hepatocellular carcinoma growth by restoring FBP1 expression

“…Loss of FBP1 has been reported in several cancers5678. Its expression in tumors is significantly lower than that in non-tumor tissues, as confirmed in gastric cancer cell lines and others671819. Restoration of its expression in cancer cells can suppress glycolysis and inhibit tumor cell proliferation.…”

Fructose-1,6-bisphosphatase Inhibits ERK Activation and Bypasses Gemcitabine Resistance in Pancreatic Cancer by Blocking IQGAP1–MAPK Interaction

“…Expression of FBP1 is downregulated in various types of cancer, including breast cancer, hepatocellular carcinoma, pancreatic cancer, renal carcinoma, lung cancer, among others (9–13). FBP1 acts as a tumor suppressor, and downregulation of FBP1 is associated with tumor progression and poor prognosis in hepatocellular carcinoma and pancreatic carcinoma.…”