Acetylated KHSRP impairs DNA-damage-response-related mRNA decay and facilitates prostate cancer tumorigenesis.

Androgen-regulated DNA damage response (DDR) is one of the essential mechanisms in prostate cancer (PCa), a hormone-sensitive disease. The heterogeneous nuclear ribonucleoprotein K (hnRNPK)-homology splicing regulatory protein known as far upstream element-binding protein 2 (KHSRP) is an RNA-binding protein that can attach to AU-rich elements in the 3' untranslated region (3'-UTR) of messenger RNAs (mRNAs) to mediate mRNA decay and emerges as a critical regulator in the DDR to preserve genome integrity. Nevertheless, how KHSRP responds to androgen-regulated DDR in PCa development remains unclear. This study found that androgen can significantly induce acetylation of KHSRP, which intrinsically drives tumor growth in xenografted mice. Moreover, enhanced KHSRP acetylation upon androgen stimuli impedes KHSRP-regulated DDR gene expression, as seen by analyzing RNA sequencing (RNA-seq) and Gene Set Enrichment Analysis (GSEA) datasets. Additionally, NAD-dependent protein deacetylase sirtuin-7 (SIRT7) is a promising deacetylase of KHSRP, and androgen stimuli impairs its interaction with KHSRP to sustain the increased KHSRP acetylation level in PCa. We first report the acetylation of KHSRP induced by androgen, which interrupts the KHSRP-regulated mRNA decay of the DDR-related genes to promote the tumorigenesis of PCa. This study provides insight into KHSRP biology and potential therapeutic strategies for PCa treatment, particularly that of castration-resistant PCa.

An urban energy recycling system that recycles the waste heat from industry for deicing on urban road in winter-taking Harbin as an example.

Northern cities in China have frequently suffered from ice and snow disasters. On the other hand, Harbin mainly relies on coal-fired plants for heating during the winter time. However, coal-fired plants produce a significant amount of air pollution through the production of numerous hazardous gases. This thesis proposed an urban energy recycling system that uses waste gas from heating facilities to recycle waste heat and reduce air pollution in northern cities during the winter. This research made a hypothesis that wintertime ice and snow on city streets could be melted by using waste heat of waste gases from heating industries. The methodology of this research can be divided into three parts: Firstly, the principle of the energy recycling system is designed based on investigation. Secondly, a simulation experiment is used to analyze the system's difficulties. According to the experiment, when an icy road is far away from the heating industry, ice melting efficiency is low. Finally, this research proposed a method for system improvement based on the findings of the experiment. The system's environmental and social benefits will likely lead to its future application in northern Chinese cities even if there are many application-related difficulties, such as the high cost of construction.

Comprehensive transcriptomics and metabolomics analyses reveal that hyperhomocysteinemia is a high risk factor for coronary artery disease in a chinese obese population aged 40-65: a prospective cross-sectional study.

BACKGROUND: Clinical observations suggest a complex relationship between obesity and coronary artery disease (CAD). This study aimed to characterize the intermediate metabolism phenotypes among obese patients with CAD and without CAD. METHODS: Sixty-two participants who consecutively underwent coronary angiography were enrolled in the discovery cohort. Transcriptional and untargeted metabolomics analyses were carried out to screen for key molecular changes between obese patients with CAD (CAD obese), without CAD (Non-CAD obese), and Non-CAD leans. A targeted GC-MS metabolomics approach was used to further identify differentially expressed metabolites in the validation cohorts. Regression and receiver operator curve analysis were performed to validate the risk model. RESULTS: We found common aberrantly expressed pathways both at the transcriptional and metabolomics levels. These pathways included cysteine and methionine metabolism and arginine and proline metabolism. Untargeted metabolomics revealed that S-adenosylhomocysteine (SAH), 3-hydroxybenzoic acid, 2-hydroxyhippuric acid, nicotinuric acid, and 2-arachidonoyl glycerol were significantly elevated in the CAD obese group compared to the other two groups. In the validation study, targeted cysteine and methionine metabolomics analyses showed that homocysteine (Hcy), SAH, and choline were significantly increased in the CAD obese group compared with the Non-CAD obese group, while betaine, 5-methylpropanedioic acid, S-adenosylmethionine, 4-PA, and vitamin B2 (VB2) showed no significant differences. Multivariate analyses showed that Hcy was an independent predictor of obesity with CAD (hazard ratio 1.7; 95%CI 1.2-2.6). The area under the curve based on the Hcy metabolomic (HCY-Mtb) index was 0.819, and up to 0.877 for the HCY-Mtb.index plus clinical variables. CONCLUSION: This is the first study to propose that obesity with hyperhomocysteinemia is a useful intermediate metabolism phenotype that could be used to identify obese patients at high risk for developing CAD.

Fbxo45-mediated NP-STEP46 degradation via K6-linked ubiquitination sustains ERK activity in lung cancer.

Lung cancer is one of the most threatening malignant tumors to human health. Epidermal growth factor receptor (EGFR)-targeted therapy is a common and essential means for the clinical treatment of lung cancer. However, drug resistance has always affected the therapeutic effect and survival rate in non-small cell lung cancer (NSCLC). Tumor heterogeneity is a significant reason, yielding various drug resistance mechanisms, such as EGFR-dependent or -independent extracellular signal-regulated kinase 1 and/or 2 (ERK1/2) activation in NSCLC. To examine whether this aberrant activation of ERK1/2 is related to the loss of function of its specific phosphatase, a series of in vitro and in vivo assays were performed. We found that F-box/SPRY domain-containing protein 1 (Fbxo45) induces ubiquitination of NP-STEP46 , an active form of striatal-enriched protein tyrosine phosphatase, with a K6-linked poly-ubiquitin chain. This ubiquitination led to proteasome degradation in the nucleus, which then sustains the aberrant level of phosphorylated-ERK (pERK) and promotes tumor growth of NSCLC. Fbxo45 silencing can significantly inhibit cell proliferation and tumor growth. Moreover, NSCLC cells with silenced Fbxo45 showed great sensitivity to the EGFR tyrosine kinase inhibitor (TKI) afatinib. Here, we first report this critical pERK maintenance mechanism, which might be independent of the upstream kinase activity in NSCLC. We propose that inhibiting Fbxo45 may combat the issue of drug resistance in NSCLC patients, especially combining with EGFR-TKI therapy.

Positive feedback between ROS and cis-axis of PIASxα/p38α-SUMOylation/MK2 facilitates gastric cancer metastasis.

MAPK/p38 is an important mammalian signaling cascade that responds to a variety of intracellular or extracellular stimuli, such as reactive oxygen species (ROS), and participates in numerous physiological and pathological processes. However, the biological function of p38 in different tumors, and even at different stages of the same tumor, remains elusive. To further understand the regulatory mechanism of p38 and oxidative stress in the occurrence and development of gastric cancer, we report SUMOylation as a novel post-translational modification occurring on lysine 152 of MAPK14/p38α through immunoprecipitation and series of pull-down assays in vitro and in vivo. Importantly, we determine that p38α-SUMOylation functions as an authentic sensor and accelerator of reactive oxygen species generation via interaction with and activation of MK2 in the nucleus, and the ROS accumulation, in turn, promotes the SUMOylation of p38α by stabilizing the PIASxα protein. This precise regulatory mechanism is exploited by gastric cancer cells to create an internal environment for survival and, ultimately, metastasis. This study reveals novel insights into p38α-SUMOylation and its association with the intracellular oxidative stress response, which is closely related to the processes of gastric cancer. Furthermore, the PIASxα/p38α-SUMOylation/MK2 cis-axis may serve as a desirable therapeutic target in gastric cancer as targeting PIASxα, MK2, or a specific peptide region of p38α may reconcile the aberrant oxidative stress response in gastric cancer cells.

Neutrophil-Lymphocyte Ratio and Circulating Tumor Cells Counts Predict Prognosis in Gastrointestinal Cancer Patients.

PURPOSE: The purpose of this study is to explore the prognostic value of associating pre-treatment neutrophil-lymphocyte ratio (NLR) with circulating tumor cells counts (CTCs) in patients with gastrointestinal cancer. MATERIALS AND METHODS: We collected the related data of 72 patients with gastric cancer (GC) and colorectal cancer (CRC) who received different therapies from August 2016 to October 2020, including age, gender, primary tumor location, TNM stage, tumor-differentiation, NLR, CTCs, disease-free survival (DFS) and overall survival (OS). We chose the optimal cut-off value of NLR >3.21 or NLR ≤3.21 and CTC >1 or CTC ≤1 by obtaining receiver operating characteristic (ROC) curve. The Kaplan-Meier survival analysis and Cox regression analysis were used to analyze DFS and OS. To clarify the role of the combination of NLR and CTCs counts in predicting the prognosis, we analyzed the DFS and OS when associated NLR and CTCs counts. RESULTS: A high NLR (>3.21) was associated with shorter DFS (P <0.0001) and OS (P <0.0001). Patients with high CTCs level (>1) had shorter DFS (P = 0.001) and OS (P = 0.0007) than patients with low CTCs level. Furthermore, patients who had both higher NLR and higher CTCs counts had obvious shorter DFS (P <0.0001) and OS (P <0.0001). CONCLUSIONS: Patients with higher NLR and more CTCs respectively tended to have poor prognosis with shorter DFS and OS, which might be regarded as predictors of gastrointestinal cancer. In particular, associating NLR and CTCs counts might be a reliable predictor in patients with gastrointestinal cancer.

Wide-bound salt tolerance of the inocula from marine sediment and their specific microbial community.

The microorganisms in marine sediment are promising candidates for the treatment of the saline wastes due to their property of salt tolerance. However, the knowledge about the microbial community and property of the marine sediments is still limited. In the present study, the salt tolerance of the microorganisms in the marine sediment that was collected from a marine fish farm was investigated by being used as inoculum for anaerobic digestion. The microbial communities were analyzed by high-throughput sequencing. The inoculum from the wastewater plant (IWTP) was taken as a control. The inoculum from the marine sediment (IMS) showed excellent capacity for anaerobic digestion at salinities of 0.3%-6%. Even at a salinity of 9%, the methane yield remained 60% of the highest yield. IMS provides promising microbial resources for the treatment of both fresh-water and saliferous organic wastes. While the IWTP was sensitive to salt, the methane yield decreased to 56% of the highest yield at the salinity of 3%. The bacterial taxonomic richness of IMS was about half of that in IWTP. Eighty-one genera were identified only in IWTP but not in IMS. The IMS possessed fewer bacterial members related to the nitrogen cycle than IWTP, but more members related to the sulfur cycle. The members of animal parasites or symbionts in IMS were significantly fewer than those in IWTP. The archaeal compositions of IMS and IWTP were different. The relative abundance of the unidentified archaea in IMS was much higher than that in IWTP with 12.52% vs 0.06% at phylum level. The findings of this work expand our understanding of the microorganisms in marine sediments and will promote the application of them in waste treatment.

SUMOylation is essential for Sirt2 tumor-suppressor function in neuroblastoma.

SUMOylation is an important post-translational modification that participates in a variety of cellular physiological and pathological processes in eukaryotic cells. Sirt2, a NAD+-dependent deacetylase, usually exerts a tumor-suppressor function. However, the role of SUMOylation in cancer cells is not fully known. In this study, we found that SUMOylation can occur in the Sirt2 protein at both lysine 183 and lysine 340 sites. SUMOylation did not affect Sirt2 localization or stability but was involved in P38-mTORC2-AKT cellular signal transduction via direct deacetylation on a new substrate MAPK/P38. SUMOylation-deficient Sirt2 lost the capability of suppressing tumor processes and showed resistance to the Sirt2-specific inhibitor AK-7 in neuroblastoma cells. Here, we revealed the important function of Sirt2-SUMOylation, which is closely associated with cellular signal transduction and is essential for suppressing tumorigenesis in neuroblastoma.

The ubiquitin system: orchestrating cellular signals in non-small-cell lung cancer.

The ubiquitin system, known as a common feature in eukaryotes, participates in multiple cellular processes, such as signal transduction, cell-cycle progression, receptor trafficking and endocytosis, and even the immune response. In lung cancer, evidence has revealed that aberrant events in ubiquitin-mediated processes can cause a variety of pathological outcomes including tumorigenesis and metastasis. Likewise, ubiquitination on the core components contributing to the activity of cell signaling controls bio-signal turnover and cell final destination. Given this, inhibitors targeting the ubiquitin system have been developed for lung cancer therapies and have shown great prospects for clinical application. However, the exact biological effects and physiological role of the drugs used in lung cancer therapies are still not clearly elucidated, which might seriously impede the progress of treatment. In this work, we summarize current research advances in cell signal regulation processes mediated through the ubiquitin system during the development of lung cancer, with the hope of improving the therapeutic effects by means of aiming at efficient targets.