FMR1NB Involved in Glioma Tumorigenesis Is a Promising Target for Prognosis and Therapy.

OBJECTIVE: Cancer/testis antigen FMR1NB is aberrantly expressed in various types of cancer, but not in normal tissues except for testis. This study aimed to investigate the expression and functional role of FMR1NB in glioma. METHODS: The expression of FMR1NB mRNA and protein was determined using RT-PCR and immunohistochemistry, respectively, in glioma specimens from 83 patients at follow-up. The effects of siRNA-mediated FMR1NB silencing on malignant biological behaviors were evaluated in glioma cell lines A172 and U251. RESULTS: FMR1NB mRNA and protein expression was detected in 58.8% (77/131) and 46.34% (57/123) of glioma tissues, respectively. FMR1NB protein was positively correlated with World Health Organization grade and found to be an independent prognostic marker for poor outcome. Knockdown of FMR1NB induced apoptosis and suppressed proliferation, adhesion, migration, and invasion by modulating the expression of cyclin A, CDK2, caspase-3, E-cadherin, and N-cadherin in A172 and U251 cells. CONCLUSION: Our findings suggest that FMR1NB contributes to the tumorigenesis of glioma cells and may represent a potential prognostic biomarker and an attractive therapeutic target in glioma.

Genomic Structure of Hstx2 Modifier of Prdm9-Dependent Hybrid Male Sterility in Mice.

F1 hybrids between mouse inbred strains PWD and C57BL/6 represent the most thoroughly genetically defined model of hybrid sterility in vertebrates. Hybrid male sterility can be fully reconstituted from three components of this model, the Prdm9 gene, intersubspecific homeology of Mus musculus musculus and Mus musculus domesticus autosomes, and the X-linked Hstx2 locus. Hstx2 modulates the extent of Prdm9-dependent meiotic arrest and harbors two additional factors responsible for intersubspecific introgression-induced oligospermia (Hstx1) and meiotic recombination rate (Meir1). To facilitate positional cloning and to overcome the recombination suppression within the 4.3 Mb encompassing the Hstx2 locus, we designed Hstx2-CRISPR and SPO11/Cas9 transgenes aimed to induce DNA double-strand breaks specifically within the Hstx2 locus. The resulting recombinant reduced the Hstx2 locus to 2.70 Mb (chromosome X: 66.51-69.21 Mb). The newly defined Hstx2 locus still operates as the major X-linked factor of the F1 hybrid sterility, and controls meiotic chromosome synapsis and meiotic recombination rate. Despite extensive further crosses, the 2.70 Mb Hstx2 interval behaved as a recombination cold spot with reduced PRDM9-mediated H3K4me3 hotspots and absence of DMC1-defined DNA double-strand-break hotspots. To search for structural anomalies as a possible cause of recombination suppression, we used optical mapping and observed high incidence of subspecies-specific structural variants along the X chromosome, with a striking copy number polymorphism of the microRNA Mir465 cluster. This observation together with the absence of a strong sterility phenotype in Fmr1 neighbor (Fmr1nb) null mutants support the role of microRNA as a likely candidate for Hstx2.

Epigenetic drug combination induced the expression of FMR1NB in oral carcinoma / 安徽医科大学学报

Objective @#To investigate the effects of DNA demethylation drugs combined with histone deacetylase inhibitors on fragile X mental retardation 1 neighbor protein (FMR1NB) expression and its promoter methylation in human oral cancer cells and try to find a strategy of weakening the heterogeneity of FMR1NB expression .@*Methods@#Human oral cancer cell lines C al27 and SCC⁃9 were treated with decitabine (DAC) , an inhibitor of DNA methyltransferase , combined with trichostatin A ( TSA) and valproic acid ( VPA) , inhibitors of histone deacetylase . Then reverse transcription⁃polymerase chain reaction ( RT⁃PCR) , quantitative real ⁃time PCR ( qRT⁃PCR) and Western blot were used to detect the expression of FMR1NB and pyrosequencing was used to detect the methylation of FMR1NB promoter. @*Results @#Compared with the blank control group , DAC and its combination with TSA and VPA significantly induced the expression of FMR1NB mRNA and protein in C al27 and SCC⁃9 cells . Compared with DAC alone group , FMR1NB mRNA expression of each DAC⁃combined drug groups significantly increased , but FMR1NB protein did not significantly change in C al27 cells; for SCC⁃9 cells , except for DAC + TSA group , the mRNA and protein levels of FMR1NB significantly increased in all other groups . In addition , there was no significant difference in the expression of FMR1NB mRNA and protein between the three⁃combined drugs group and two-combined drugs groups . Further methylation assay showed that the methylation level of the overall FMR1NB promoter and its each CpG site measured were reduced to varying degrees in all treatment groups except for three⁃combination drug group of SCC⁃9 .@*Conclusion @#DAC and its combination with TSA and VPA can enhance the expression of FMR1NB by mediating the demethylation of FMR1NB promoter , wherein the enhanced expression effect of the combination of the two drugs is stronger , suggesting that they have the potential to weaken the heterogeneity of FMR1NB expression and improve the immunotherapy effect of oral cancer.