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The aldolase family members involved in metabolism and glycolysis are present in three isoforms: ALDOA, ALDOB, and ALDOC. Aldolases are differentially expressed in human tissues, and aberrant expression has been observed in several human diseases and cancer types. However, non-enzymatic functions through protein-protein interactions or epigenetic modifications have been reported in recent years. Using high-throughput screening and -omics database integration, aldolase has been validated as an independent clinical prognostic marker of human cancers. Therefore, the aim of this review was to provide potential clinical value from in silico predictions and also summarize well-known signaling axes or phenotypes in various cancer types. Finally, we discuss the role of aldolase in the treatment of human diseases and cancers.

Cancer cells encounter metabolic stresses such as hypoxia and nutrient limitations because they grow and divide more quickly than their normal counterparts. In response to glucose restriction, we found that nuclear translocation of the glycolic enzyme, pyruvate kinase M2 (PKM2), helped cancer cells survive under the metabolic stress. Restriction of glucose stimulated AMPK activation and resulted in co-translocation of AMPK and PKM2 through Ran-mediated nuclear transport. Nuclear PKM2 subsequently bound to Oct4 and promoted the expression of cancer stemness-related genes, which might enrich the cancer stem cell population under the metabolic stress. Nuclear PKM2 was also capable of promoting cancer metastasis in an orthotopic xenograft model. In summary, we found that cytosolic AMPK helped PKM2 carry out its nonmetabolic functions in the nucleus under glucose restriction and that nuclear PKM2 promoted cancer stemness and metastasis. These findings suggested a potential new targeting pathway for cancer therapy in the future.

Graphene has shown many attractive properties while the difficulties in the fabrication of high-quality graphene have been a significant bottleneck in its applications. Here we report the discovery of high-quality graphene obtained from the solidified equiatomic CrFeCoNiC high-entropy alloy. Graphite flakes can be peeled off from the surface of the as-cast CrFeCoNiC high-entropy alloy, and single or multilayer graphene can be further exfoliated. The mechanical properties of the graphene are investigated by an atomic force microscope, and the result confirms the discovery of high-quality graphene. The transmission electron microscopy and Raman spectroscopy are applied to further characterize the quality of the graphene and show that the graphene has high-quality with few defects, comparable to the graphene obtained from highly oriented pyrolytic graphite. The thermodynamic calculation is applied to investigate the solidification process of the high-entropy alloy and reveals the mechanism of the formation of graphite on the surface.

KH-type splicing regulatory protein (KSRP) is a single-strand RNA binding protein which regulates mRNA stability either by binding to AU-rich elements (AREs) of mRNA 3'UTR or by facilitating miRNA biogenesis to target mRNA. Unlike its well-characterized function at the molecular level in maintaining RNA homeostasis, the role of KSRP in cancer progression remains largely unknown. Here we investigate the role of KSRP in non-small cell lung cancer (NSCLC). We first examined KSRP expression by immunohistochemistry in a cohort containing 196 NSCLC patients and observed a strong positive correlation between KSRP expression and survival of NSCLC patients. Multivariate analysis further identified KSRP as an independent prognostic factor. Manipulating KSRP expression significantly affected in vitro cell mobility and in vivo metastatic ability of NSCLC cells. Microarray analysis identified an ARE-containing gene, EGR3, as a downstream effector of KSRP in NSCLC. Interestingly, we found that KSRP decreased EGR3 mRNA stability in an ARE-independent manner. By screening KSRP-regulated miRNAs in NSCLC cells, we further found that miR-23a directly binds to EGR3 3'UTR, reducing EGR3 expression and thereby inhibiting NSCLC cell mobility. Our findings implicate a targetable KSRP/miR-23a/EGR3 signaling axis in advanced tumor phenotypes.

Background: Monoamine oxidases (MAOs) are enzymes located on the outer membrane of mitochondria that catalyze monoamine oxidation. Recently, increased expression levels of MAOs have been shown in several cancer types. However, the possible roles of MAOs in the progression and prognosis of colorectal cancer have not yet been elucidated. Methods: We analyzed the role and importance of MAOs in colorectal cancer via an online database analysis and by using tumor tissue microarray. Findings: Several independent colorectal cancer cohorts indicated that high expression of monoamine oxidase B (MAOB) but not of MAOA correlated with worse disease stage and poorer survival. A tissue microarray of 203 cases of colorectal cancer underwent immunohistochemical staining for MAOs and the results were evaluated for the associations with clinicopathological parameters and patient outcomes. High expression of MAOB in primary tumor tissue was observed in 114 samples and was significantly correlated with poor prognosis in colorectal cancer patients (p = 0.002). Moreover, via multivariate analyses, overexpression of MAOB remained an independent prognostic factor for overall survival (p = 0.006) and disease-free survival (p = 0.009). However, the correlation between MAOA expression and these parameters was not significant in colorectal cancer patients. Interpretation: In this study, a significant positive correlation between MAOB and mesenchymal-type gene expression was also found. According to the highlighted characteristics of MAOB in colorectal cancer, MAOB can be used as an independent poor prognostic indicator for colorectal cancer. Funding: This study was supported by the Ministry of Science and Technology, Taiwan, R.O.C. Declaration of Interest: The authors have declared no conflicts of interest. Ethical Approval: The study was carried out with the approval of the Institutional Review Board of WanFang Hospital (Approval No. 99047) and permission from the ethics committees of the institution involved.

Introduction DNA methyltransferase 3B (DNMT3B) contributes to de novo DNA methylation and its overexpression promotes tumorigenesis. However, whether DNMT3B is upregulated by transcriptional deregulation remains unclear. Methods We studied the transcriptional repression of DNMT3B by forkhead O transcription factor 3a (FOXO3a) in lung cancer cell, animal, and clinical models. Results The results of luciferase reporter assay showed that FOXO3a negatively regulated DNMT3B promoter activity by preferentially interacting with the binding element FOXO3a-E (+166 to +173) of DNMT3B promoter. Ectopically overexpressed FOXO3a or combined treatment with doxorubicin to induce FOXO3a nuclear accumulation further bound at the distal site, FOXO3a-P (−249 to −242) by chromatin-immunoprecipitation assay. Knockdown of FOXO3a resulted in an open chromatin structure and high DNMT3B mRNA and protein expression. Abundant FOXO3a repressed DNMT3B promoter by establishing a repressed chromatin structure. Note that FOXO3a is a degradation substrate of MDM2 E3-ligase. Cotreatment with doxorubicin and MDM2 inhibitor, Nutlin-3, further enforced abundant nuclear accumulation of FOXO3a resulting in decrease expression of DNMT3B leading to synergistic inhibition of tumor growth and decrease of methylation status on tumor suppressor genes in xenograft specimens. Clinically, lung cancer patients with DNMT3B high, FOXO3a low, and MDM2 high expression profile correlated with poor prognosis examined by immunohistochemistry and Kaplan-Meier survival analysis. Conclusions We reveal a new mechanism that FOXO3a transcriptionally represses DNMT3B expression and this regulation can be attenuated by MDM2 overexpression in human lung cancer model. Cotreatment with doxorubicin and Nutlin-3 is a novel therapeutic strategy through epigenetic modulation.