Design, Synthesis, and Antiproliferative Activity of Selective Histone Deacetylases 6 Inhibitors Containing a Tetrahydropyridopyrimidine Scaffold.

The development of selective histone deacetylase 6 inhibitors (sHDAC6is) is being recognized as a therapeutic approach for cancers. In this paper, we designed a series of novel tetrahydropyridopyrimidine derivatives as sHDAC6 inhibitors. The most potent compound, 8-(2, 4-bis(3-methoxyphenyl)-5, 8-dihydropyrido [3, 4-d]pyrimidin-7(6H)-yl)-N-hydroxy-8-oxooctanamide (8f), inhibited HDAC6 with IC50 of 6.4 nM, and showed > 48-fold selectivity over other subtypes. In Western blot assay, 8f elevated the levels of acetylated α-tubulin in a dose-dependent manner. In vitro, 8f inhibited RPMI-8226, HL60, and HCT116 tumor cells with IC50 of 2.8, 3.20, and 3.25 µM, respectively. Moreover, 8f showed good antiproliferative activity against a panel of tumor cells.

FOXD3-induced miR-133a blocks progression and metastasis of colorectal cancer through regulating UBA2.

Background and Aim: Some studies have verified that miR-133a played an inhibitory role in several cancers. Whereas, the effect of miRNA-133a in colorectal cancer (CRC) has not been fully elucidated. Our study aims to confirm UBA2 as a direct target gene of miRNA-133a and explore the upstream modulatory molecules of miR-133a. In addition, their impacts on the biological characteristics of CRC cells were assessed. Methods: QRT-PCR analyzed miR-133a expression levels in colorectal cells including HCT116, SW48 cells and human normal colorectal cell line NCM460. A serial biological experiment assessed miR-133a effects on cell proliferation, migration, invasion and apoptosis capacities in HCT116 and SW48 cells. MiRNA targeting gene prediction and a dual luciferase assay were employed to confirm miR-133a-targeted UBA2. Transcription factors (TFs) FOXD3 was identified as an upstream regulator of miR-133a via JASPAR. The influence of miR-133a and FOXD3 on UBA2 expression was analyzed by qRT-PCR or western blot. Results: miR-133a was lowly expressed in CRC cells. High miRNA-133a expression suppressed the proliferation, migration, invasion and enhanced apoptosis capacities of CRC cells. MiR-133a targeted the UBA2 mRNA 3'UTR area and reduced UBA2 protein expression. We also unveiled that FOXD3 high-expression significantly raised miR-133a expression and diminished UBA2 expression. We also discovered that high miR-133a expression augmented the effects of elevated FOXD3 expression on CRC cell proliferation, migration and invasion, whereas, low miR-133a expression generated the opposite outcomes. Conclusion: FOXD3 induced miRNA-133a directly targeting UBA2 could affect the progression and growth of CRC.

Construction of Immune-Associated Nomogram for Predicting the Recurrence Survival Risk of Stage I Cervical Cancer.

BACKGROUND: Various studies reported that the prognosis of patients with cervical cancer (CC) was significantly associated with immunity, whereas limited studies have explored whether immune-associated genes could be classifiers for recurrence-free survival (RFS) of stage I CC. Thus, an improved immune-related gene signature for stage I CC patients' prognosis is urgently required. MATERIALS AND METHODS: We retrospectively analyzed the gene expression profiles of stage I CC patients in the GSE44001 set from the Gene Expression Omnibus (GEO) database. The stage I CC patients were randomly divided into the training group and the internal validation group. The training patients were adopted to develop a prognostic immune gene-based signature; meanwhile, the internal validation patients were used to validate the power of the selected immune gene-related signature using univariate Cox proportional hazard analysis, least absolute shrinkage and selection operator (LASSO), and multivariate Cox regression analysis. The accuracy and reliability of the immune gene-related signature were evaluated based on Kaplan-Meier analysis and time-dependent receiver operating characteristic (ROC) curves. RESULTS: High power of the 8-immune gene signature was found on the basis of ROC analysis (AUC at 1, 3, and 5 years were exhibited in the internal validation group (0.702, 0.715, and 0.728, respectively), external validation group (0.702, 0.825, and 0.842, respectively), and entire GEO dataset (0.840, 0.894, and 0.852, respectively)). Besides, C-index, ROC, calibration plots, and decision curve analysis (DCA) also acted well in our nomogram, suggestive of a high ability of the nomogram to elevate the prognostic prediction of stage I CC patients. CONCLUSIONS: In this study, we successfully constructed an integrated 8-immune gene-based signature which could accurately identify patients with low prognostic risk from those with high prognostic risk. In addition, we developed an immune-related nomogram which can elevate the prognostic prediction of stage I CC patients.

Breeding signatures of rice improvement revealed by a genomic variation map from a large germplasm collection.

Intensive rice breeding over the past 50 y has dramatically increased productivity especially in the indica subspecies, but our knowledge of the genomic changes associated with such improvement has been limited. In this study, we analyzed low-coverage sequencing data of 1,479 rice accessions from 73 countries, including landraces and modern cultivars. We identified two major subpopulations, indica I (IndI) and indica II (IndII), in the indica subspecies, which corresponded to the two putative heterotic groups resulting from independent breeding efforts. We detected 200 regions spanning 7.8% of the rice genome that had been differentially selected between IndI and IndII, and thus referred to as breeding signatures. These regions included large numbers of known functional genes and loci associated with important agronomic traits revealed by genome-wide association studies. Grain yield was positively correlated with the number of breeding signatures in a variety, suggesting that the number of breeding signatures in a line may be useful for predicting agronomic potential and the selected loci may provide targets for rice improvement.

The Phosphate Transporter Gene OsPht1;4 Is Involved in Phosphate Homeostasis in Rice.

A total of 13 phosphate transporters in rice (Oryza sative) have been identified as belonging to the Pht1 family, which mediates inorganic phosphate (Pi) uptake and transport. We report the biological property and physiological role of OsPht1;4 (OsPT4). Overexpressing OsPT4 resulted in significant higher Pi accumulation in roots, straw and brown rice, and suppression of OsPT4 caused decreased Pi concentration in straw and brown rice. Expression of the ß-glucuronidase reporter gene driven by the OsPT4 promoter showed that OsPT4 is expressed in roots, leaves, ligules, stamens, and caryopses under sufficient Pi conditions, consistent with the expression profile showing that OsPT4 has high expression in roots and flag leaves. The transcript level of OsPT4 increased significantly both in shoots and roots with a long time Pi starvation. OsPT4 encoded a plasma membrane-localized protein and was able to complement the function of the Pi transporter gene PHO84 in yeast. We concluded that OsPT4 is a functional Pi-influx transporter involved in Pi absorption in rice that might play a role in Pi translocation. This study will enrich our understanding about the physiological function of rice Pht1 family genes.

Genome-wide association analyses provide genetic and biochemical insights into natural variation in rice metabolism.

Plant metabolites are important to world food security in terms of maintaining sustainable yield and providing food with enriched phytonutrients. Here we report comprehensive profiling of 840 metabolites and a further metabolic genome-wide association study based on ∼6.4 million SNPs obtained from 529 diverse accessions of Oryza sativa. We identified hundreds of common variants influencing numerous secondary metabolites with large effects at high resolution. We observed substantial heterogeneity in the natural variation of metabolites and their underlying genetic architectures among different subspecies of rice. Data mining identified 36 candidate genes modulating levels of metabolites that are of potential physiological and nutritional importance. As a proof of concept, we functionally identified or annotated five candidate genes influencing metabolic traits. Our study provides insights into the genetic and biochemical bases of rice metabolome variation and can be used as a powerful complementary tool to classical phenotypic trait mapping for rice improvement.

OsNRAMP5 contributes to manganese translocation and distribution in rice shoots.

Manganese (Mn) is an essential micronutrient for plants playing an important role in many physiological functions. OsNRAMP5 is a major transporter responsible for Mn and cadmium uptake in rice, but whether it is involved in the root-to-shoot translocation and distribution of these metals is unknown. In this work, OsNRAMP5 was found to be highly expressed in hulls. It was also expressed in leaves but the expression level decreased with leaf age. High-magnification observations revealed that OsNRAMP5 was enriched in the vascular bundles of roots and shoots especially in the parenchyma cells surrounding the xylem. The osnramp5 mutant accumulated significantly less Mn in shoots than the wild-type plants even at high levels of Mn supply. Furthermore, a high supply of Mn could compensate for the loss in the root uptake ability in the mutant, but not in the root-to-shoot translocation of Mn, suggesting that the absence of OsNRAMP5 reduces the transport of Mn from roots to shoots. The results suggest that OsNRAMP5 plays an important role in the translocation and distribution of Mn in rice plants in addition to its role in Mn uptake.