Case report: ISL2 is involved in malignant transformation in a patient with multiple relapsed oligodendroglioma.

The majority of oligodendrogliomas exhibit an intrinsic tendency to develop into malignant high-grade tumors. Angiogenesis is a major factor contributing to the malignant transformation of oligodendroglioma, and its molecular regulatory mechanism needs further study. We provide a case report of an oligodendroglioma patient with two recurrences whose disease progressed from WHO grade II to grade III. We showed that the expression of insulin gene enhancer protein (ISL2) and its angiogenic ability were positively correlated with the progression of oligodendroglioma. In Low-grade glioma (LGG) patients, including oligodendroglioma patients, overexpression of ISL2 was correlated with poor prognosis, and this correlation was not affected by gender or isocitrate dehydrogenase 1(IDH1) mutation status. ISL2 expression and ISL2-mediated angiogenic pathway activity are ideal biomarkers for the malignant transformation of oligodendroglioma. Anti-ISL2 therapy is also a potential treatment option for malignantly transformed oligodendroglioma.

p53 coordinates glucose and choline metabolism during the mesendoderm differentiation of human embryonic stem cells.

Metabolism plays crucial roles in the fate decision of human embryonic stem cells (hESCs). Here, we show that the depletion of p53 in hESCs enhances glycolysis and reduces oxidative phosphorylation, and delays mesendoderm differentiation of hESCs. More intriguingly, the disruption of p53 in hESCs leads to dramatic upregulation of phosphatidylcholine and decrease of total choline in both pluripotent and differentiated state of hESCs, suggesting abnormal choline metabolism in the absence of p53. Collectively, our study reveals the indispensable role of p53 in orchestrating both glucose and lipid metabolism to maintain proper hESC identity.

MTR4 drives liver tumorigenesis by promoting cancer metabolic switch through alternative splicing.

The metabolic switch from oxidative phosphorylation to glycolysis is required for tumorigenesis in order to provide cancer cells with energy and substrates of biosynthesis. Therefore, it is important to elucidate mechanisms controlling the cancer metabolic switch. MTR4 is a RNA helicase associated with a nuclear exosome that plays key roles in RNA processing and surveillance. We demonstrate that MTR4 is frequently overexpressed in hepatocellular carcinoma (HCC) and is an independent diagnostic marker predicting the poor prognosis of HCC patients. MTR4 drives cancer metabolism by ensuring correct alternative splicing of pre-mRNAs of critical glycolytic genes such as GLUT1 and PKM2. c-Myc binds to the promoter of the MTR4 gene and is important for MTR4 expression in HCC cells, indicating that MTR4 is a mediator of the functions of c-Myc in cancer metabolism. These findings reveal important roles of MTR4 in the cancer metabolic switch and present MTR4 as a promising therapeutic target for treating HCC.

Core pluripotency factors promote glycolysis of human embryonic stem cells by activating GLUT1 enhancer.

Human embryonic stem cells (hESCs) depend on glycolysis for energy and substrates for biosynthesis. To understand the mechanisms governing the metabolism of hESCs, we investigated the transcriptional regulation of glucose transporter 1 (GLUT1, SLC2A1), a key glycolytic gene to maintain pluripotency. By combining the genome-wide data of binding sites of the core pluripotency factors (SOX2, OCT4, NANOG, denoted SON), chromosomal interaction and histone modification in hESCs, we identified a potential enhancer of the GLUT1 gene in hESCs, denoted GLUT1 enhancer (GE) element. GE interacts with the promoter of GLUT1, and the deletion of GE significantly reduces the expression of GLUT1, glucose uptake and glycolysis of hESCs, confirming that GE is an enhancer of GLUT1 in hESCs. In addition, the mutation of SON binding motifs within GE reduced the expression of GLUT1 as well as the interaction between GE and GLUT1 promoter, indicating that the binding of SON to GE is important for its activity. Therefore, SON promotes glucose uptake and glycolysis in hESCs by inducing GLUT1 expression through directly activating the enhancer of GLUT1.

20-hydroxyecdysone positively regulates the transcription of the antimicrobial peptide, lebocin, via BmEts and BmBR-C Z4 in the midgut of Bombyx mori during metamorphosis.

Metamorphosis is an essential physiological process in insects. This process is triggered by 20-hydroxyecydsone (20E). Lebocin, an antimicrobial peptide of Lepidoptera insects, was significantly up-regulated in the midgut, but not in the fat body of Bombyx mori during metamorphosis. In this study, the expression regulation of lebocin in B. mori midgut was studied. The results showed that B. mori lebocin and its activator BmEts were not responsive to bacterial infection in the midgut, instead, the expression of both genes was up-regulated by 20E treatment. The transcription factor BR-C Z4 in the 20E signal pathway enhanced lebocin promoter activity by directly binding to an upstream cis-response element of the promoter. In the fat body, the mRNA level of B. mori lebocin was decreased when the insect transformed from larval to pupal stage and was increased by immune challenge. The expression profiles of lebocin in Lepidopteran Spodoptera litura was also analyzed and the similar results were observed, S. litura lebocin was significantly up-regulated during midgut regeneration and mainly present in the new-formed intestinal cells of the midgut. All results together suggest that during metamorphosis 20E may activate lebocin expression via BmBR-C Z4 and BmEts in the midgut, where the antimicrobial peptide was produced to protect the midgut from infection.