The oncogene c‐Myc is aberrantly expressed and plays a key role in malignant transformation and progression of hepatocellular carcinoma (HCC). Here, we report that c‐Myc is significantly up‐regulated ...by tumor necrosis factor receptor–associated factor 6 (TRAF6), an E3 ubiquitin ligase, in hepatocarcinogenesis. High TRAF6 expression in clinical HCC samples correlates with poor prognosis, and the loss of one copy of the Traf6 gene in Traf6+/– mice significantly impairs liver tumorigenesis. Mechanistically, TRAF6 first interacts with and ubiquitinates histone deacetylase 3 (HDAC3) with K63‐linked ubiquitin chains, which leads to the dissociation of HDAC3 from the c‐Myc promoter and subsequent acetylation of histone H3 at K9, thereby epigenetically enhancing the mRNA expression of c‐Myc. Second, the K63‐linked ubiquitination of HDAC3 impairs the HDAC3 interaction with c‐Myc and promotes c‐Myc protein acetylation, which thereby enhances c‐Myc protein stability by inhibiting carboxyl terminus of heat shock cognate 70‐kDa–interacting protein–mediated c‐Myc ubiquitination and degradation. Importantly, TRAF6/HDAC3/c‐Myc signaling is also primed in hepatitis B virus–transgenic mice, unveiling a critical role for a mechanism in inflammation–cancer transition. In clinical specimens, TRAF6 positively correlates with c‐Myc at both the mRNA and protein levels, and high TRAF6 and c‐Myc expression is associated with an unfavorable prognosis, suggesting that TRAF6 collaborates with c‐Myc to promote human hepatocarcinogenesis. Consistently, curbing c‐Myc expression by inhibition of TRAF6 activity with a TRAF6 inhibitor peptide or the silencing of c‐Myc by small interfering RNA significantly suppressed tumor growth in mice. Conclusion: These findings demonstrate the oncogenic potential of TRAF6 during hepatocarcinogenesis by modulating TRAF6/HDAC3/c‐Myc signaling, with potential implications for HCC therapy.
α‐Alkoxy enones are quite useful building blocks in organic chemistry. The existing methods for syntheses of these compounds remain somewhat limited. Over the past years, nucleophilic phosphine ...catalysis has emerged as a practical and powerful tool for constructing diverse molecules with the advantages of environmental‐friendly, metal‐free, and mild reaction conditions. Meanwhile, alkynone is easy to prepare, can undergo a variety of reactions, and is a commonly used substrate for organic synthesis. α‐Addition of alcohols to alkynones is a direct way to construct α‐alkoxy enones. In this study, it was delightful to find that using PPh3 (10 mmol %) and 1,1,1,3,3,3‐hexafluoroisopropanol (HFIP) (20 mmol %) could redirect from β‐addition to α‐addition. With this approach, a variety of α‐alkoxy enones could be obtained directly with good yields and regioselectivity. Under optimal conditions, the generality of the reaction was investigated. Substrate scope studies showed that the reaction was well tolerated with many alcohols. Mechanistic study is also demonstrated.
The α‐addition of alcohols to alkynones was demonstrated. A series of α‐alkoxy enones can directly be synthesized in moderate to high yields under mild conditions. Mechanism studies were carried out by various means.
The class III deacetylase sirtuin 1 (SIRT1), a member of the sirtuin family proteins, plays a key role in many types of cancers including colorectal cancer (CRC). Here we report that SIRT1 suppressed ...CRC metastasis in vitro and in vivo as a negative regulator for miR-15b-5p transcription. Mechanistically, SIRT1 impaired regulatory effects of activator protein (AP-1) on miR-15b-5p trans-activation through deacetylation of AP-1. Importantly, acyl-CoA oxidase 1 (ACOX1), a key enzyme of the fatty acid oxidation (FAO) pathway, was found as a direct target for miR-15b-5p. SIRT1 expression was positively correlated with ACOX1 expression in CRC cells and in xenografts. Moreover, ACOX1 overexpression attenuated the augmentation of migration and invasion of CRC cells by miR-15b-5p overexpression. In conclusion, our study demonstrated a functional role of the SIRT1/miR-15b-5p/ACOX1 axis in CRC metastasis and suggested a potential target for metastatic CRC therapy.
•SIRT1 is a tumor suppressor gene in colorectal cancer patients.•SIRT1 suppresses CRC metastasis by blocking miR-15b-5p transcription.•SIRT1 suppresses miR-15b-5p transcription by impairing the binding of AP-1 to its promoter.•SIRT1 inhibits CRC metastasis through SIRT1/miR-15b-5p/ACOX1 axis.
Sugars are essential regulatory molecules involved in plant growth and development and defense response. Although the relationship between sugars and disease resistance has been widely discussed, the ...underlying molecular mechanisms remain unexplored. Ring rot caused by Botryosphaeria dothidea (B. dothidea), which severely affects fruit quality and yield, is a destructive disease of apples (Malus domestica Borkh.). The present study found that the degree of disease resistance in apple fruit was closely related to glucose content. Therefore, the gene encoding a hexokinase, MdHXK1, was isolated from the apple cultivar 'Gala', and characterized during the defense response. Overexpression of MdHXK1 enhanced disease resistance in apple calli, leaves and fruits by increasing the expression levels of genes related to salicylate (SA) synthesis (PHYTOALEXIN DEFICIENT 4, PAD4; PHENYLALANINE AMMONIA‐LYASE, PAL; and ENHANCED DISEASE SUSCEPTIBILITY 1, EDS1) and signaling (PR1; PR5; and NONEXPRESSER OF PR GENES 1, NPR1) as well as increasing the superoxide (O2−) production rate and the hydrogen peroxide (H2O2) content. Overall, the study provides new insights into the MdHXK1‐mediated molecular mechanisms by which glucose signaling regulates apple ring rot resistance.
Ubiquitin specific protease 4 (USP4) is a deubiquitinating enzyme with key roles in the regulation of p53 and TGFβ signaling, suggesting its importance in tumorigenesis. However, the mechanisms and ...regulatory roles of USP4 in cancer, including colorectal cancer, remain largely elusive. Here, we present the first evidence that USP4 regulates the growth, invasion, and metastasis of colorectal cancer. USP4 expression was significantly elevated in colorectal cancer tissues and was significantly associated with tumor size, differentiation, distant metastasis, and poor survival. Knockdown of USP4 diminished colorectal cancer cell growth, colony formation, migration, and invasion in vitro and metastasis in vivo. Importantly, we found that phosphatase of regenerating liver-3 (PRL-3) is indispensable for USP4-mediated oncogenic activity in colorectal cancer. Mechanistically, we observed that USP4 interacted with and stabilized PRL-3 via deubiquitination. This resulted in activation of Akt and reduction of E-cadherin, critical regulators of cancer cell growth and metastasis. Examination of clinical samples confirmed that USP4 expression positively correlates with PRL-3 protein expression, but not mRNA transcript levels. Taken together, our results demonstrate that aberrant expression of USP4 contributes to the development and progression of colorectal cancer and reveal a critical mechanism underlying USP4-mediated oncogenic activity. These observations suggest that the potential of harnessing proteolytic degradation processes for therapeutic manipulation may offer a much-needed new approach for improving colorectal cancer treatment strategies.
Ubiquitination is a basic post-translational modification for cellular homeostasis, and members of the conjugating enzyme (E2) family are the key components of the ubiquitin-proteasome system. ...However, the role of E2 family in colorectal cancer (CRC) is largely unknown. Our study aimed to investigate the role of Ube2v1, one of the ubiquitin-conjugating E2 enzyme variant proteins (Ube2v) but without the conserved cysteine residue required for the catalytic activity of E2s, in CRC.
Immunohistochemistry and real-time RT-PCR were used to study the expressions of Ube2v1 at protein and mRNA levels in CRC, respectively. Western blotting and immunofluorescence, transmission electron microscopy, and in vivo rescue experiments were used to study the functional effects of Ube2v1 on autophagy and EMT program. Quantitative mass spectrometry, immunoprecipitation, ubiquitination assay, western blotting, and real-time RT-PCR were used to analyze the effects of Ube2v1 on histone H4 lysine 16 acetylation, interaction with Sirt1, ubiquitination of Sirt1, and autophagy-related gene expression.
Ube2v1 was elevated in CRC samples, and its increased expression was correlated with poorer survival of CRC patients. Ube2v1 promoted migration and invasion of CRC cells in vitro and tumor growth and metastasis of CRC cells in vivo. Interestingly, Ube2v1suppressed autophagy program and promoted epithelial mesenchymal transition (EMT) and metastasis of CRC cells in an autophagy-dependent pattern in vitro and in vivo. Moreover, both rapamycin and trehalose attenuated the enhanced Ube2v1-mediated lung metastasis by inducing the autophagy pathway in an orthotropic mouse xenograft model of lung metastasis. Mechanistically, Ube2v1 promoted Ubc13-mediated ubiquitination and degradation of Sirt1 and inhibited histone H4 lysine 16 acetylation, and finally epigenetically suppressed autophagy gene expression in CRC.
Our study functionally links Ube2v1, an E2 member in the ubiquitin-proteasome system, to autophagy program, thereby shedding light on developing Ube2v1 targeted therapy for CRC patients.
Temperature is one of the most important environmental factors affecting the physiological activities and, thus, the fitness of fish, and physiological studies can help predict the effects of climate ...change on fish species in the field. The aim of this study was to investigate the effect of acclimation temperature on the thermal tolerance, hypoxia tolerance and swimming ability of two endangered fish species in the upper reach of the Yangtze River, namely, the Chinese sucker (
Myxocyprinus asiaticus
) and rock carp (
Procypris rabaudi
). The fish were acclimated at either 15 °C or 25 °C for a 3-week period. Then, thermal tolerance as indicated by the critical thermal maximum (CT
max
) and critical thermal minimum (CT
min
), hypoxia tolerance as indicated by the aquatic surface respiration (ASR
50
) and loss of equilibrium (LOE
50
), swimming performance as indicated by the critical swimming speed (
U
crit
), aerobic capacity as indicated by the maximum metabolic rate and aerobic scope were measured. As expected, the thermal indicators of both species increased with temperature, and their values at both acclimation temperatures were similar to those of fish living in the Yangtze River. However, both species showed poor hypoxia tolerance compared to most fish species in the Yangtze River, according to previous studies. In particular, Chinese sucker acclimated at a low temperature exhibited an unusually strong decrease in hypoxia tolerance with decreasing temperature (fish usually showed high hypoxia tolerance due to decreased oxygen demand and high environmental oxygen tension at low temperature). Furthermore, Chinese sucker exhibited poorer swimming performance than rock carp (which is also a relatively poor swimmer among the fish species in the Yangtze River) when maintained at a high temperature due to low swimming efficiency, possibly as a consequence of its deep body shape. The difference in
U
crit
was magnified at low temperature due to the more profound decrease in metabolic scope in Chinese sucker than in rock carp (55% vs 20%), but Chinese sucker showed a higher resting metabolic rate than rock carp at a low temperature, which is difficult to explain. This result suggested that low hypoxia tolerance and poor swimming performance due to the low cardiorespiratory capacity and (or) non-streamlined body shape of both fish species, especially Chinese sucker, reared at low temperature might be two of the reasons why they are not well adjusted to the change in their natural habitat and have thus declined in recent decades. The underlying physiological and biochemical mechanisms involved in the unusual adjustment of the physiological function of Chinese sucker and its ecological relevance must be investigated further. The present study provides a good example of a physiological investigation yielding very interesting and useful data for species conservation in a changing world.
Electric-LC resonators (ELCs) metamaterials, as a kind of common structures, have been extensively investigated from microwave to terahertz frequencies. In this paper, we present a LC circuit model ...to analyze electric-LC resonator. With the reliable and closed
formulas of the effective inductance and capacitance, the expressions of electric and magnetic resonance frequencies were obtained, which is suitable to discuss the resonance characteristic under the normal incidence case. Meanwhile, the mutual relationships among the permittivity, permeability, refractive index, and structure parameters can be explored by using the obtained expressions. Numerical simulations and theoretical calculations reveal that the width and length of the gaps are some of the critical parameters determining the resonator frequency of the example metamaterial. This
study provides valuable information for designing the desired left-hand metamaterial at some specific frequency points.
Nitrogen is not only an essential nutrient for plant, but also an important signal molecule to integrate and regulate gene expression, metabolism and growth. Plant peptides are considered as a new ...type of hormone, and play an important regulatory role in plant growth and development. However, little is known about the co-regulation network between nitrogen and peptide hormones in plant. Here we identified an apple
MdCLE8
gene, which encodes a putative peptide, induced by nitrogen deficiency in apple. Ectopic expression of
MdCLE8
inhibited lateral root formation in
Arabidopsis
under nitrogen deficiency. Similarly, overexpression of
MdCLE8
inhibited lateral root development in apple adventitious roots, and this inhibition was amplified under nitrogen deficiency treatment. Further studies showed that
MdCLE8
may inhibit the expression of several key genes during lateral root emergence stage in
Arabidopsis
, thereby inhibiting the emergence of lateral root from root cortex cells. Collectively, our study not only broadened the gene regulatory network under the influence of nitrogen in apple, but also expanded the function of CLE peptide hormones in apple.
Key message
The apple peptide encoding gene
MdCLE8
is induced by nitrogen deficiency signaling and negatively regulates lateral root formation in plants.
PDF
