Inhibition of FBP1 expression by KMT5A through TWIST1 methylation is one of the mechanisms leading to chemoresistance in breast cancer.

Lysine methyltransferase 5A (KMT5A) is the sole mammalian enzyme known to catalyse the mono­methylation of histone H4 lysine 20 and non­histone proteins such as p53, which are involved in the occurrence and progression of numerous cancers. The present study aimed to determine the function of KMT5A in inducing docetaxel (DTX) resistance in patients with breast carcinoma by evaluating glucose metabolism and the underlying mechanism involved. The upregulation or downregulation of KMT5A­related proteins was examined after KMT5A knockdown in breast cancer (BRCA) cells by Tandem Mass Tag proteomics. Through differential protein expression and pathway enrichment analysis, the upregulated key gluconeogenic enzyme fructose­1,6­bisphosphatase 1 (FBP1) was discovered. Loss of FBP1 expression is closely related to the development and prognosis of cancers. A dual­luciferase reporter gene assay confirmed that KMT5A inhibited the expression of FBP1 and that overexpression of FBP1 could enhance the chemotherapeutic sensitivity to DTX through the suppression of KMT5A expression. The KMT5A inhibitor UNC0379 was used to verify that DTX resistance induced by KMT5A through the inhibition of FBP1 depended on the methylase activity of KMT5A. According to previous literature and interaction network structure, it was revealed that KMT5A acts on the transcription factor twist family BHLH transcription factor 1 (TWIST1). Then, it was verified that TWSIT1 promoted the expression of FBP1 by using a dual­luciferase reporter gene experiment. KMT5A induces chemotherapy resistance in BRCA cells by promoting cell proliferation and glycolysis. After the knockdown of the KMT5A gene, the FBP1 related to glucose metabolism in BRCA was upregulated. KMT5A knockdown expression and FBP1 overexpression synergistically inhibit cell proliferation and block cells in the G2/M phase. KMT5A inhibits the expression of FBP1 by methylating TWIST1 and weakening its promotion of FBP1 transcription. In conclusion, KMT5A was shown to affect chemotherapy resistance by regulating the cell cycle and positively regulate glycolysis­mediated chemotherapy resistance by inhibiting the transcription of FBP1 in collaboration with TWIST1. KMT5A may be a potential therapeutic target for chemotherapy resistance in BRCA.

MiR827 positively regulates the resistance to chilli veinal mottle virus by affecting the expression of FBPase in Nicotiana benthamiana.

MicroRNA(miRNA) is a class of non-coding small RNA that plays an important role in plant growth, development, and response to environmental stresses. Unlike most miRNAs, which usually target homologous genes across a variety of species, miR827 targets different types of genes in different species. Research on miR827 mainly focuses on its role in regulating phosphate (Pi) homeostasis of plants, however, little is known about its function in plant response to virus infection. In the present study, miR827 was significantly upregulated in the recovery tissue of virus-infected Nicotiana tabacum. Overexpression of miR827 could improve plants resistance to the infection of chilli veinal mottle virus (ChiVMV) in Nicotiana benthamiana, whereas interference of miR827 increased the susceptibility of the virus-infected plants. Further experiments indicated that the antiviral defence regulated by miR827 was associated with the reactive oxygen species and salicylic acid signalling pathways. Then, fructose-1,6-bisphosphatase (FBPase) was identified to be a target of miR827, and virus infection could affect the expression of FBPase. Finally, transient expression of FBPase increased the susceptibility to ChiVMV-GFP infection in N. benthamiana. By contrast, silencing of FBPase increased plant resistance. Taken together, our results demonstrate that miR827 plays a positive role in tobacco response to virus infection, thus providing new insights into understanding the role of miR827 in plant-virus interaction.

FBP1 orchestrates keratinocyte proliferation/differentiation and suppresses psoriasis through metabolic control of histone acetylation.

Keratinocyte proliferation and differentiation in epidermis are well-controlled and essential for reacting to stimuli such as ultraviolet light. Imbalance between proliferation and differentiation is a characteristic feature of major human skin diseases such as psoriasis and squamous cell carcinoma. However, the effect of keratinocyte metabolism on proliferation and differentiation remains largely elusive. We show here that the gluconeogenic enzyme fructose-1,6-bisphosphatase 1 (FBP1) promotes differentiation while inhibits proliferation of keratinocyte and suppresses psoriasis development. FBP1 is identified among the most upregulated genes induced by UVB using transcriptome sequencing and is elevated especially in upper epidermis. Fbp1 heterozygous mice exhibit aberrant epidermis phenotypes with local hyperplasia and dedifferentiation. Loss of FBP1 promotes proliferation and inhibits differentiation of keratinocytes in vitro. Mechanistically, FBP1 loss facilitates glycolysis-mediated acetyl-CoA production, which increases histone H3 acetylation at lysine 9, resulting in enhanced transcription of proliferation genes. We further find that the expression of FBP1 is dramatically reduced in human psoriatic lesions and in skin of mouse imiquimod psoriasis model. Fbp1 deficiency in mice facilitates psoriasis-like skin lesions development through glycolysis and acetyl-CoA production. Collectively, our findings reveal a previously unrecognized role of FBP1 in epidermal homeostasis and provide evidence for FBP1 as a metabolic psoriasis suppressor.

DNA methyltransferase 3a-induced hypermethylation of the fructose-1,6-bisphosphatase-2 promoter contributes to gastric carcinogenesis.

BACKGROUND: Aberrant DNA methylation has been implicated in the development of gastric cancer (GC). In our previous study, we demonstrated that fructose-1,6-bisphosphatase-2 (FBP2), an enzyme that suppresses cell glycolysis and growth, is downregulated in GC due to promoter methylation. However, the precise mechanism underlying this process remains unknown. Thus, this study aimed to elucidate the mechanisms involved in FBP2 promoter hypermethylation. METHODS AND RESULTS: The methylation levels in GC and normal adjacent tissues were quantified using methylation-specific polymerase chain reaction. FBP2 promoter was frequently hypermethylated in primary GC tissues compared to adjacent normal tissues. To explore the functional consequences of this hypermethylation, we employed small interfering RNA-mediated knockdown of DNA methyltransferase 3a (DNMT3a) in GC cells. FBP2 expression increased following DNMT3a knockdown, suggesting that reduced methylation of the FBP2 promoter contributed to this upregulation. To further investigate this interaction, chromatin immunoprecipitation assays were conducted. The results confirmed an interaction between DNMT3a and the FBP2 promoter region, providing evidence that DNMT3a-mediated hypermethylation of the FBP2 promoter promotes GC progression. CONCLUSIONS: This study provides evidence that DNMT3a is involved in the hypermethylation of the FBP2 promoter and regulation of GC cell metabolism. Hypermethylation of the FBP2 promoter may be a promising prognostic biomarker in GC.

Fructose-1,6-bisphosphatase is a nonenzymatic safety valve that curtails AKT activation to prevent insulin hyperresponsiveness.

Insulin inhibits gluconeogenesis and stimulates glucose conversion to glycogen and lipids. How these activities are coordinated to prevent hypoglycemia and hepatosteatosis is unclear. Fructose-1,6-bisphosphatase (FBP1) is rate controlling for gluconeogenesis. However, inborn human FBP1 deficiency does not cause hypoglycemia unless accompanied by fasting or starvation, which also trigger paradoxical hepatomegaly, hepatosteatosis, and hyperlipidemia. Hepatocyte FBP1-ablated mice exhibit identical fasting-conditional pathologies along with AKT hyperactivation, whose inhibition reversed hepatomegaly, hepatosteatosis, and hyperlipidemia but not hypoglycemia. Surprisingly, fasting-mediated AKT hyperactivation is insulin dependent. Independently of its catalytic activity, FBP1 prevents insulin hyperresponsiveness by forming a stable complex with AKT, PP2A-C, and aldolase B (ALDOB), which specifically accelerates AKT dephosphorylation. Enhanced by fasting and weakened by elevated insulin, FBP1:PP2A-C:ALDOB:AKT complex formation, which is disrupted by human FBP1 deficiency mutations or a C-terminal FBP1 truncation, prevents insulin-triggered liver pathologies and maintains lipid and glucose homeostasis. Conversely, an FBP1-derived complex disrupting peptide reverses diet-induced insulin resistance.

Fructose-1,6-bisphosphatase 1 dephosphorylates IκBα and suppresses colorectal tumorigenesis.

Emerging evidence demonstrates that some metabolic enzymes that phosphorylate soluble metabolites can also phosphorylate a variety of protein substrates as protein kinases to regulate cell cycle, apoptosis and many other fundamental cellular processes. However, whether a metabolic enzyme dephosphorylates protein as a protein phosphatase remains unknown. Here we reveal the gluconeogenic enzyme fructose 1,6-biphosphatase 1 (FBP1) that catalyzes the hydrolysis of fructose 1,6-bisphosphate (F-1,6-BP) to fructose 6-phosphate (F-6-P) as a protein phosphatase by performing a high-throughput screening of metabolic phosphatases with molecular docking followed by molecular dynamics (MD) simulations. Moreover, we identify IκBα as the substrate of FBP1-mediated dephosphorylation by performing phosphoproteomic analysis. Mechanistically, FBP1 directly interacts with and dephosphorylates the serine (S) 32/36 of IκBα upon TNFα stimulation, thereby inhibiting NF-κB activation. MD simulations indicate that the catalytic mechanism of FBP1-mediated IκBα dephosphorylation is similar to F-1,6-BP dephosphorylation, except for higher energetic barriers for IκBα dephosphorylation. Functionally, FBP1-dependent NF-κB inactivation suppresses colorectal tumorigenesis by sensitizing tumor cells to inflammatory stresses and preventing the mobilization of myeloid-derived suppressor cells. Our finding reveals a previously unrecognized role of FBP1 as a protein phosphatase and establishes the critical role of FBP1-mediated IκBα dephosphorylation in colorectal tumorigenesis.

Expression of fructose-1,6-bisphosphatase 1 is associated with [18F]FDG uptake and prognosis in patients with mesial temporal lobe epilepsy.

OBJECTIVES: To determine whether fructose-1,6-bisphosphatase 1 (FBP1) expression is associated with [18F]FDG PET uptake and postsurgical outcomes in patients with mesial temporal lobe epilepsy (mTLE) and to investigate whether the molecular mechanism involving gamma-aminobutyric acid type A receptor (GABAAR), glucose transporter-3 (GLUT-3), and hexokinase-II (HK-II). METHODS: Forty-three patients with mTLE underwent [18F]FDG PET/CT. Patients were divided into Ia (Engel class Ia) and non-Ia (Engel class Ib-IV) groups according to more than 1 year of follow-up after surgery. The maximum standard uptake value (SUVmax) and asymmetry index (AI) of hippocampus were measured. The relationship among the SUVmax, AI, prognosis, and FBP1 expression was analyzed. A lithium-pilocarpine acute mTLE rat model was subjected to [18F]FDG micro-PET/CT. Hippocampal SUVmax and FBP1, GABAAR, GLUT-3, and HK-II expression were analyzed. RESULTS: SUVmax was higher in the Ia group than in the non-Ia group (7.31 ± 0.97 vs. 6.56 ± 0.96, p < 0.05) and FBP1 expression was lower in the Ia group (0.24 ± 0.03 vs. 0.27 ± 0.03, p < 0.01). FBP1 expression was negatively associated with SUVmax and AI (p < 0.01). In mTLE rats, the hippocampal FBP1 increased (0.26 ± 0.00 vs. 0.17 ± 0.00, p < 0.0001), and SUVmax, GLUT-3 and GABAAR levels decreased significantly (0.73 ± 0.12 vs. 1.46 ± 0.23, 0.20 ± 0.01 vs. 0.32 ± 0.05, 0.26 ± 0.02 vs. 0.35 ± 0.02, p < 0.05); no significant difference in HK-II levels was observed. In mTLE patients and rats, FBP1 negatively correlated with SUVmax and GLUT-3 and GABAAR levels (p < 0.05). CONCLUSION: FBP1 expression was inversely associated with SUVmax in mTLE, which might inhibit [18F]FDG uptake by regulating GLUT-3 expression. High FBP1 expression was indicative of low GABAAR expression and poor prognosis. KEY POINTS: • It is of paramount importance to explore the deep pathophysiological mechanisms underlying the pathogenesis of mesial temporal lobe epilepsy and find potential therapeutic targets. • [18F]FDG PET has demonstrated low metabolism in epileptic regions during the interictal period, and hypometabolism may be associated with prognosis, but the pathomechanism of this association remains uncertain. • Our results support the possibility that FBP1 might be simultaneously involved in the regulation of glucose metabolism levels and the excitability of neurons and suggest that targeting FBP1 may be a viable strategy in the diagnosis and treatment of mesial temporal lobe epilepsy.

Fructose-1,6-bisphosphatase 1 functions as a protein phosphatase to dephosphorylate histone H3 and suppresses PPARα-regulated gene transcription and tumour growth.

Tumour cells exhibit greater metabolic plasticity than normal cells and possess selective advantages for survival and proliferation with unclearly defined mechanisms. Here we demonstrate that glucose deprivation in normal hepatocytes induces PERK-mediated fructose-1,6-bisphosphatase 1 (FBP1) S170 phosphorylation, which converts the FBP1 tetramer to monomers and exposes its nuclear localization signal for nuclear translocation. Importantly, nuclear FBP1 binds PPARα and functions as a protein phosphatase that dephosphorylates histone H3T11 and suppresses PPARα-mediated ß-oxidation gene expression. In contrast, FBP1 S124 is O-GlcNAcylated by overexpressed O-linked N-acetylglucosamine transferase in hepatocellular carcinoma cells, leading to inhibition of FBP1 S170 phosphorylation and enhancement of ß-oxidation for tumour growth. In addition, FBP1 S170 phosphorylation inversely correlates with ß-oxidation gene expression in hepatocellular carcinoma specimens and patient survival duration. These findings highlight the differential role of FBP1 in gene regulation in normal and tumour cells through direct chromatin modulation and underscore the inactivation of its protein phosphatase function in tumour growth.

FBP1-Altered Carbohydrate Metabolism Reduces Leukemic Viability through Activating P53 and Modulating the Mitochondrial Quality Control System In Vitro.

Acute myeloid leukemia (AML)-the most frequent form of adult blood cancer-is characterized by heterogeneous mechanisms and disease progression. Developing an effective therapeutic strategy that targets metabolic homeostasis and energy production in immature leukemic cells (blasts) is essential for overcoming relapse and improving the prognosis of AML patients with different subtypes. With respect to metabolic regulation, fructose-1,6-bisphosphatase 1 (FBP1) is a gluconeogenic enzyme that is vital to carbohydrate metabolism, since gluconeogenesis is the central pathway for the production of important metabolites and energy necessary to maintain normal cellular activities. Beyond its catalytic activity, FBP1 inhibits aerobic glycolysis-known as the "Warburg effect"-in cancer cells. Importantly, while downregulation of FBP1 is associated with carcinogenesis in major human organs, restoration of FBP1 in cancer cells promotes apoptosis and prevents disease progression in solid tumors. Recently, our large-scale sequencing analyses revealed FBP1 as a novel inducible therapeutic target among 17,757 vitamin-D-responsive genes in MV4-11 or MOLM-14 blasts in vitro, both of which were derived from AML patients with FLT3 mutations. To investigate FBP1's anti-leukemic function in this study, we generated a new AML cell line through lentiviral overexpression of an FBP1 transgene in vitro (named FBP1-MV4-11). Results showed that FBP1-MV4-11 blasts are more prone to apoptosis than MV4-11 blasts. Mechanistically, FBP1-MV4-11 blasts have significantly increased gene and protein expression of P53, as confirmed by the P53 promoter assay in vitro. However, enhanced cell death and reduced proliferation of FBP1-MV4-11 blasts could be reversed by supplementation with post-glycolytic metabolites in vitro. Additionally, FBP1-MV4-11 blasts were found to have impaired mitochondrial homeostasis through reduced cytochrome c oxidase subunit 2 (COX2 or MT-CO2) and upregulated PTEN-induced kinase (PINK1) expressions. In summary, this is the first in vitro evidence that FBP1-altered carbohydrate metabolism and FBP1-activated P53 can initiate leukemic death by activating mitochondrial reprogramming in AML blasts, supporting the clinical potential of FBP1-based therapies for AML-like cancers.

The role of LINC01419 in regulating the cell stemness in lung adenocarcinoma through recruiting EZH2 and regulating FBP1 expression.

BACKGROUND: Recent years have witnessed a growing academic interest in the effects of lncRNAs on tumors. LINC01419 is found to facilitate proliferation and metastasis of lung adenocarcinoma (LUAD) cells, but there is a great deal of uncertainty about how LINC01419 works on LUAD cell stemness. For this reason, the focus of this research is centered on the regulatory impact of LINC01419 on LUAD cell stemness. METHODS: For the detection of the expression level of LINC01419 in LUAD, qRT-PCR was performed. And how oe-LINC01419 and sh-LINC01419 affected LUAD cell proliferation as well as stem cell sphere-formation were examined by CCK-8 and cell sphere-forming assays. In addition, whether LINC01419 could recruit EZH2 and regulate FBP1 expression were determined by bioinformatics analysis, RNA immunoprecipitation (RIP), and chromatin immunoprecipitation (ChIP). Western blot was utilized to detect the protein expression levels of FBP1, CD44, CD133, and ALDH-1 as well. RESULTS: On the basis of the findings from those assays, an up-regulation of LINC01419 level was demonstrated in LUAD cell lines, and a remarkable upregulation of it in CD44 + LUAD cells. In LUAD cells, proliferation and stem cell sphere-formation that were attenuated by LINC01419 knockdown were discovered to be facilitated by LINC01419 overexpression. And a binding relationship between LINC01419 and EZH2 was determined by RIP assay. Besides, EZH2 was capable of binding to FBP1 promoter region, as found by ChIP-PCR assay. Finally, it was demonstrated by in vitro experiments that LINC01419 could inhibit FBP1 expression by recruiting EZH2, resulting in promotion of LUAD cell proliferation and stemness. SIGNIFICANCE: To summarize, our findings demonstrate a cancer-promoting role of LINC01419 in LUAD. LINC01419, by recruiting EZH2 and regulating FBP1 expression, contributes to LUAD cell stemness. According to these findings, the potential of LINC01419 to be the target for LUAD treatment is hence determined, which also adds more possibility to the enrichment of therapeutic strategies for lung cancer stem cells.

FBP1 knockdown decreases ovarian cancer formation and cisplatin resistance through EZH2-mediated H3K27me3.

Worldwide, ovarian cancer (OC) is the seventh common cancer and the second most common cause of cancer death in women. Due to high rates of relapse, there is an urgent need for the identification of new targets for OC treatment. The far-upstream element binding protein 1 (FBP1) and enhancer of zeste homolog 2 (EZH2) are emerging proto-oncogenes that regulate cell proliferation and metastasis. In the present study, Oncomine data analysis demonstrated that FBP1 was closely associated with the development of OC, and The Cancer Genome Atlas (TCGA) data analysis indicated that there was a positive correlation between FBP1 and EZH2 in ovarian tissues. Moreover, we found that FBP1 knockdown suppressed tumor formation in nude mice and cisplatin resistance of OC cells, but the role of FBP1 in the cisplatin resistance of OC cells remained unclear. In addition, we verified physical binding between FBP1 and EZH2 in OC cells, and we demonstrated that FBP1 knockdown enhanced cisplatin cytotoxicity in OC cells and down-regulated EZH2 expression and trimethylation of H3K27. These results suggested that FBP1 increases cisplatin resistance of OC cells by up-regulating EZH2/H3K27me3. Thus, FBP1 is a prospective novel target for the development of OC treatment.

Epigenetic regulation of Fructose-1,6-bisphosphatase 1 by host transcription factor Speckled 110 kDa during hepatitis B virus infection.

Hepatitis B virus (HBV) is the leading cause of liver disease ranging from acute and chronic hepatitis to liver cirrhosis and hepatocellular carcinoma (HCC). Studies have revealed that HBV infection broadly reprogrammes the host cellular metabolic processes for viral pathogenesis. Previous reports have shown that glycolysis and gluconeogenesis are among the most deregulated pathways during HBV infection. We noted that despite being one of the rate-limiting enzymes of gluconeogenesis, the role and regulation of Fructose-1,6-bisphosphatase 1 (FBP1) during HBV infection is not much explored. In this study, we report FBP1 upregulation upon HBV infection and unravel a novel mechanism of epigenetic reprogramming of FBP1 by HBV via utilizing host factor Speckled 110 kDa (Sp110). Here, we identified acetylated lysine 18 of histone H3 (H3K18Ac) as a selective interactor of Sp110 Bromodomain. Furthermore, we found that Sp110 gets recruited on H3K18Ac-enriched FBP1 promoter, and facilitates recruitment of deacetylase Sirtuin 2 (SIRT2) on that site in the presence of HBV. SIRT2 in turn brings its interactor and transcriptional activator Hepatocyte nuclear factor 4-alpha to the promoter, which ultimately leads to a loss of DNA methylation near the cognate site. Interestingly, this Sp110 driven FBP1 regulation during infection was found to promote viral-borne HCC progression. Moreover, Sp110 can be used as a prognostic marker for the hepatitis-mediated HCC patients, where high Sp110 expression significantly lowered their survival. Thus, the epigenetic reader protein Sp110 has potential to be a therapeutic target to challenge HBV-induced HCCs.

Fructose-1,6-Bisphosphatase 2 Inhibits Oral Squamous Cell Carcinoma Tumorigenesis and Glucose Metabolism via Downregulation of c-Myc.

Background: Fructose-1,6-bisphosphatase 2 (FBP2), known as a rate-limiting enzyme in gluconeogenesis, is a tumor suppressor downregulated in various cancers. However, the role of FBP2 in oral squamous cell carcinoma (OSCC) remains largely unclear. Methods: The level of FBP2 in OSCC tissues and matched adjacent normal tissues was determined by western blot and RT-qPCR assays. In addition, analysis of FBP2 function in OSCC cells was assessed using both gain-of-function and loss-of-function studies. Results: In this study, we found that the expression of FBP2 was remarkably downregulated in OSCC tissues and OSCC cells. Overexpression of FBP2 suppressed the viability, proliferation, migration, and glycolysis of OSCC cells, whereas FBP2 knockdown exhibited the opposite results. Moreover, downregulation of FBP2 promoted the growth and glycolysis of OSCC cells in nude mice in a xenograft model. Specifically, FBP2 colocalizes with the c-Myc transcription factor in the nucleus. Significantly, inhibitory effects of FBP2 overexpression on the viability, proliferation, migration, and glycolysis of OSCC cells were reversed by c-Myc overexpression. Conclusion: Collectively, FBP2 could suppress the proliferation, migration and glycolysis in OSCC cells through downregulation of c-Myc. Our study revealed a FBP2-c-Myc signaling axis that regulates OSCC glycolysis and may provide a potential intervention strategy for OSCC treatment.

Fructose-1,6-bisphosphatase 1 (FBP1) is an independent biomarker associated with a favorable prognosis in esophageal adenocarcinoma.

INTRODUCTION: Despite modern multimodal therapeutic regimens, the prognosis of esophageal adenocarcinoma (EAC) is still poor and there is a lack of biological markers estimating the patients' prognosis. Fructose-1,6-biphosphatase (FBP1) is a key enzyme in gluconeogenesis and is associated with tumor initiation in several cancers. Therefore, this study aims to characterize its implication for EAC patients. METHODS AND MATERIALS: A total of 571 EAC patients who underwent multimodal treatment between 1999 and 2017 were analyzed for FBP1 expression using immunohistochemistry. RESULTS: 82.5% of the EACs show FBP1 expression in the tumor albeit with different intensities categorizing specimens accordingly into score 0 (no expression), score 1 (weak expression), score 2 (moderate expression) and score 3 (strong expression) (score 1 = 25.0%, score 2 = 35.9%, score 3 = 21.5%). Intratumoral FBP1 expression was significantly associated with a better prognosis (p = 0.024). This observation was particularly relevant among patients who received primary surgery without neoadjuvant treatment (p = 0.004). In multivariate analysis, elevated FBP1 expression was an independent biomarker associated with a favorable prognosis. DISCUSSION: Despite being associated with a favorable prognosis, the majority of patients with high FBP1 expression also require individualized therapy options to ensure long-term survival. Recently, it has been shown that the presence of the FBP1 protein increases the sensitivity of pancreatic cancer cells to the bromodomain and extraterminal domain (BET) inhibitor JQ1. CONCLUSION: We described for the first time the prognostic and possibly therapeutic relevance of FBP1 in EAC. The efficiency of the BET inhibitor in EAC should be verified in clinical studies and special attention should be paid to the effects of neoadjuvant therapy on FBP1 expression.

The role of fructose 1,6-bisphosphate-mediated glycolysis/gluconeogenesis genes in cancer prognosis.

Metabolic reprogramming and elevated glycolysis levels are associated with tumor progression. However, despite cancer cells selectively inhibiting or expressing certain metabolic enzymes, it is unclear whether differences in gene profiles influence patient outcomes. Therefore, identifying the differences in enzyme action may facilitate discovery of gene ontology variations to characterize tumors. Fructose-1,6-bisphosphate (F-1,6-BP) is an important intermediate in glucose metabolism, particularly in cancer. Gluconeogenesis and glycolysis require fructose-1,6-bisphosphonates 1 (FBP1) and fructose-bisphosphate aldolase A (ALDOA), which participate in F-1,6-BP conversion. Increased expression of ALDOA and decreased expression of FBP1 are associated with the progression of various forms of cancer in humans. However, the exact molecular mechanism by which ALDOA and FBP1 are involved in the switching of F-1,6-BP is not yet known. As a result of their pancancer pattern, the relationship between ALDOA and FBP1 in patient prognosis is reversed, particularly in lung adenocarcinoma (LUAD) and liver hepatocellular carcinoma (LIHC). Using The Cancer Genome Atlas (TCGA), we observed that FBP1 expression was low in patients with LUAD and LIHC tumors, which was distinct from ALDOA. A similar trend was observed in the analysis of Cancer Cell Line Encyclopedia (CCLE) datasets. By dissecting downstream networks and possible upstream regulators, using ALDOA and FBP1 as the core, we identified common signatures and interaction events regulated by ALDOA and FBP1. Notably, the identified effectors dominated by ALDOA or FBP1 were distributed in opposite patterns and can be considered independent prognostic indicators for patients with LUAD and LIHC. Therefore, uncovering the effectors between ALDOA and FBP1 will lead to novel therapeutic strategies for cancer patients.

Overexpression of aldolase, fructose-bisphosphate C and its association with spheroid formation in colorectal cancer.

Colorectal cancer (CRC) is a leading cause of cancer-related death worldwide. The spheroid colony formation assay is a useful method to identify cancer stem cells (CSCs). Using the DLD-1 and WiDr CRC cell lines, we performed microarray analyses of spheroid body-forming and parental cells and demonstrated that aldolase, fructose-bisphosphate C (ALDOC) was overexpressed in the spheroid body-forming cells of both lines. Cells transfected with small interfering RNA against ALDOC demonstrated lower proliferation, migration, and invasion compared with negative control cells. Both the number and size of spheres produced by the CRC cells were significantly reduced by ALDOC knockdown. Additionally, inhibition of ALDOC reduced lactate production. Immunohistochemistry was used to analyze ALDOC protein expression in tissues from 135 CRC patients and revealed that 66 (49%) cases were positive for ALDOC. The ALDOC-positive cases were associated with higher T and M grades and, as determined by Kaplan-Meier analysis, a poorer prognosis. Univariate and multivariate analyses indicated that ALDOC expression was an independent prognostic factor for CRC patients. Furthermore, ALDOC expression was associated with CD44 expression. These results suggest that ALDOC contributes to CRC progression and plays an important role in CSCs derived from CRC.

Potassium and melatonin-mediated regulation of fructose-1,6-bisphosphatase (FBPase) and sedoheptulose-1,7- bisphosphatase (SBPase) activity improve photosynthetic efficiency, carbon assimilation and modulate glyoxalase system accompanying tolerance to cadmium stress in tomato seedlings.

The mechanism of the combined action of potassium (K) and melatonin (Mel) in modulating tolerance to cadmium (Cd) stress in plants is not well understood. The present study reveals the synergistic role of K and Mel in enhancing physiological and biochemical mechanisms of Cd stress tolerance in tomato seedlings. The present findings reveal that seedlings subjected to Cd toxicity exhibited disturbed nutrients balance [nitrogen (N) and potassium (K)], chlorophyll (Chl) biosynthesis [reduced δ-aminolevulinic acid (δ-ALA) content and δ-aminolevulinic acid dehydratase (δ-ALAD) activity], pathway of carbon fixation [reduced fructose-1,6-bisphosphatase (FBPase) and sedoheptulose-1,7- bisphosphatase (SBPase) activity] and photosynthesis process in tomato seedlings. However, exogenous application of K and Mel alone as well as together improved physiological and biochemical mechanisms in tomato seedlings, but their combined application proved best by efficiently improving nutrient uptake, photosynthetic pigments biosynthesis (increased Chl a and b, and Total Chl), carbon flow in Calvin cycle, activity of Rubisco, carbonic anhydrase activity, and accumulation of total soluble carbohydrates content in seedlings under Cd toxicity. Furthermore, the combined treatment of K and Mel suppressed overproduction of reactive oxygen species (hydrogen peroxide and superoxide), Chl degradation [reduced chlorophyllase (Chlase) activity] and methylglyoxal content in Cd-stressed tomato seedlings by upregulating glyoxalase (increased glyoxalase I and glyoxalase II activity) and antioxidant systems (increased ascorbate-glutathione metabolism). Thus, the present study provides stronger evidence that the co-application of K and Mel exhibited synergistic roles in mitigating the toxic effect of Cd stress by increasing glyoxalase and antioxidant systems and also by improving photosynthetic efficiency in tomato seedlings.

Fructose-1,6-bisphosphatase deficiency causes fatty liver disease and requires long-term hepatic follow-up.

Liver disease, occurring during pediatric or adult age, is often of undetermined cause. Some cases are probably related to undiagnosed inherited metabolic disorders. Hepatic disorders associated with fructose-1,6-bisphosphatase deficiency, a gluconeogenesis defect, are not reported in the literature. These symptoms are mainly described during acute crises, and many reports do not mention them because hypoglycemia and hyperlactatemia are more frequently in the forefront. Herein, the liver manifestations of 18 patients affected with fructose-1,6-bisphosphatase deficiency are described and the corresponding literature is reviewed. Interestingly, all 18 patients had liver abnormalities either during follow-up (hepatomegaly [n = 8/18], elevation of transaminases [n = 6/15], bright liver [n = 7/11]) or during acute crises (hepatomegaly [n = 10/17], elevation of transaminases [n = 13/16], acute liver failure [n = 6/14], bright liver [n = 4/14]). Initial reports described cases of liver steatosis, when liver biopsy was necessary to confirm the diagnosis by an enzymatic study. There is no clear pathophysiological basis for this fatty liver disease but we postulate that endoplasmic reticulum stress and de novo lipogenesis activation could be key factors, as observed in FBP1 knockout mice. Liver steatosis may expose patients to severe long-term liver complications. As hypoglycemia becomes less frequent with age, most adult patients are no longer monitored by hepatologist. Signs of fructose-1,6-bisphosphatase deficiency may be subtle and can be missed in childhood. We suggest that fructose-1,6-bisphosphatase deficiency should be considered as an etiology of hepatic steatosis, and a liver monitoring protocol should be set up for these patients, during lifelong follow-up.

Fructose-1,6-bisphosphatase 2 represses cervical cancer progression via inhibiting aerobic glycolysis through promoting pyruvate kinase isozyme type M2 ubiquitination.

Growing evidence has shown that aerobic glycolysis, as a hallmark of cancer cells, plays a crucial role in cervical cancer. The aim of the study is to uncover whether fructose-1,6-bisphosphatase 2 (FBP2) is involved in cervical cancer progression via the aerobic glycolysis pathway. FBP2 levels were determined by quantitative PCR (qPCR) and western blotting. Cell growth viability and apoptosis were tested by cell counting kit-8 (CCK-8) and flow cytometry assays. Immunoprecipitation assay was applied for the detection of the FBP2 effect on pyruvate kinase isozyme type M2 (PKM2) ubiquitination. FBP2 level was decreased in cervical cancer, which is closely linked to shorter overall survival. FBP2 decreased cell growth and aerobic glycolysis and increased cell apoptosis, as well as decreased PKM2 expression and increased its ubiquitination level. The above-mentioned roles of FBP2 were weakened followed by PKM2 overexpression. FBP2 inhibited cervical cancer cell growth via inhibiting aerobic glycolysis by inducing PKM2 ubiquitination.

FBP1 regulates proliferation, metastasis, and chemoresistance by participating in C-MYC/STAT3 signaling axis in ovarian cancer.

Fructose-1,6-bisphosphatase (FBP1) is a rate-limiting enzyme in gluconeogenesis and an important tumor suppressor in human malignancies. Here, we aimed to investigate the expression profile of FBP1 in ovarian cancer, the molecular mechanisms that regulate FBP1 expression and to examine how the FBP1 regulatory axis contributes to tumorigenesis and progression in ovarian cancer. We showed that FBP1 expression was significantly decreased in ovarian cancer tissues compared with normal ovarian tissues, and low-FBP1 expression predicted poor prognosis in patients with ovarian cancer. The enhanced expression of FBP1 in ovarian cancer cell lines suppressed proliferation and 2-D/3-D invasion, reduced aerobic glycolysis, and sensitized cancer cells to cisplatin-induced apoptosis. Moreover, DNA methylation and C-MYC binding at the promoter inhibited FBP1 expression. Furthermore, through physical interactions with signal transducer and activator of transcription 3 (STAT3), FBP1 suppressed nuclear translocation of STAT3 and exerted its non-metabolic enzymatic activity to induce the dysfunction of STAT3. Thus, our study suggests that FBP1 may be a valuable prognostic predictor for ovarian cancer. C-MYC-dependent downregulation of FBP1 acted as a tumor suppressor via modulating STAT3, and the C-MYC/FBP1/STAT3 axis could be a therapeutic target.