scholarly journals Human gut-microbiome-derived propionate coordinates proteasomal degradation via HECTD2 upregulation to target EHMT2 in colorectal cancer

2022 ◽  
Author(s):  
Tae Young Ryu ◽  
Kwangho Kim ◽  
Tae-Su Han ◽  
Mi-Ok Lee ◽  
Jinkwon Lee ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
Synergistic Effects ◽  
Human Microbiome ◽  
Proteasomal Degradation ◽  
Human Immune System ◽  
Hect Domain ◽  
Ubiquitin Protein Ligase ◽  
Anticancer Effects ◽  
Culture Models ◽  
Factor Α

AbstractThe human microbiome plays an essential role in the human immune system, food digestion, and protection from harmful bacteria by colonizing the human intestine. Recently, although the human microbiome affects colorectal cancer (CRC) treatment, the mode of action between the microbiome and CRC remains unclear. This study showed that propionate suppressed CRC growth by promoting the proteasomal degradation of euchromatic histone-lysine N-methyltransferase 2 (EHMT2) through HECT domain E3 ubiquitin protein ligase 2 (HECTD2) upregulation. In addition, EHMT2 downregulation reduced the H3K9me2 level on the promoter region of tumor necrosis factor α-induced protein 1 (TNFAIP1) as a novel direct target of EHMT2. Subsequently, TNFAIP1 upregulation induced the apoptosis of CRC cells. Furthermore, using Bacteroides thetaiotaomicron culture medium, we confirmed EHMT2 downregulation via upregulation of HECTD2 and TNFAIP1 upregulation. Finally, we observed the synergistic effect of propionate and an EHMT2 inhibitor (BIX01294) in 3D spheroid culture models. Thus, we suggest the anticancer effects of propionate and EHMT2 as therapeutic targets for colon cancer treatment and may provide the possibility for the synergistic effects of an EHMT2 inhibitor and microbiome in CRC treatment.

scholarly journals Histone methyltransferase EHMT2 degradation by propionate derived from Bacteroides thetaiotaomicron induced colon cancer apoptosis via epigenetic regulation of TNFAIP1

2020 ◽  
Author(s):  
Tae Young Ryu ◽  
Kwangho Kim ◽  
Tae-Su Han ◽  
Mi-Ok Lee ◽  
Jinkwon Lee ◽  
...  
Keyword(s):  
Colon Cancer ◽  
Target Genes ◽  
Synergistic Effects ◽  
Human Microbiome ◽  
Bacteroides Thetaiotaomicron ◽  
Glycosidic Bonds ◽  
Anticancer Effects ◽  
Induced Apoptosis ◽  
Hydrolysis Of

Abstract BackgroundBacteroides thetaiotaomicron (BT) is the second most commonly isolated bacterium in the human microbiome after B. fragilis and is involved in the hydrolysis of glycosidic bonds in dietary carbohydrates. Although the human microbiome has recently been shown to affect colorectal cancer (CRC) treatment, the mode of action (MOA) between the microbiome and CRC is still unclear.MethodsTo assess the colon cancer apoptosis, we performed western blot, qRT-PCR and FACS analysis using BT supernatant (Sup), sodium propionate (SP), and EHMT2 specific siRNA. Using RNA-seq analysis and ChIP-seq analysis, we identified HECTD2 (E3 ligase) and TNFAIP1 (EHMT2 target) genes. The antitumor activity of EHMT2 was determined by an in vivo xenograft model.ResultsWe selected propionate derived from BT and showed that it suppressed CRC growth by promoting proteasomal degradation of EHMT2 through HECTD2 upregulation. Moreover, downregulation of EHMT2 reduced the level of H3K9me2 on the promoter region of TNFAIP1, and subsequently, upregulation of TNFAIP1 induced apoptosis of CRC cells. Finally, we performed an in vivo study using BIX01294 to inactivate EHMT2 and observed a reduction in the tumor size of the CRC xenograft models.ConclusionsWe suggest anticancer effects of BT and EHMT2 as therapeutic targets for colon cancer treatment, and we will provide the possibility for synergistic effects of an EHMT2 inhibitor and BT in CRC treatment.*Authors share co-first authorship

Genes Encoding Ribosomal Proteins Rps0A/B of Saccharomyces cerevisiae Interact With TOM1 Mutants Defective in Ribosome Synthesis

Genetics ◽  
2001 ◽  
Vol 157 (3) ◽  
pp. 1107-1116
Author(s):  
Amy L Tabb ◽  
Takahiko Utsugi ◽  
Clavia R Wooten-Kee ◽  
Takeshi Sasaki ◽  
Steven A Edling ◽  
...  
Keyword(s):  
Saccharomyces Cerevisiae ◽  
Ribosomal Proteins ◽  
Elevated Temperatures ◽  
Synergistic Effects ◽  
Ribosomal Subunit ◽  
Hect Domain ◽  
Ribosome Synthesis ◽  
Ubiquitin Protein Ligase ◽  
40S Ribosomal Subunit ◽  
Genes Encoding

Abstract The Saccharomyces cerevisiae RPS0A/B genes encode proteins of the 40S ribosomal subunit that are required for the maturation of 18S rRNA. We show here that the RPS0 genes interact genetically with TOM1. TOM1 encodes a member of the hect-domain-containing E3 ubiquitin-protein ligase family that is required for growth at elevated temperatures. Mutant alleles of the RPS0 and TOM1 genes have synergistic effects on cell growth at temperatures permissive for TOM1 mutants. Moreover, the growth arrest of TOM1 mutants at elevated temperatures is partially suppressed by overexpression of RPS0A/B. Strains with mutant alleles of TOM1 are defective in multiple steps in rRNA processing, and interactions between RPS0A/B and TOM1 stem, in part, from their roles in the maturation of ribosomal subunits. Ribosome synthesis is therefore included among the cellular processes governed by members of the hect-domain-containing E3 ubiquitin-protein ligase family.

Phytosomal Curcumin Elicits Anti-tumor Properties Through Suppression of Angiogenesis, Cell Proliferation and Induction of Oxidative Stress in Colorectal Cancer

2019 ◽  
Vol 24 (39) ◽  
pp. 4626-4638 ◽  
Author(s):  
Reyhaneh Moradi-Marjaneh ◽  
Seyed M. Hassanian ◽  
Farzad Rahmani ◽  
Seyed H. Aghaee-Bakhtiari ◽  
Amir Avan ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
Colorectal Cancer ◽  
Therapeutic Potential ◽  
Vegf Signaling ◽  
Anticancer Effects ◽  
Inhibition Of Angiogenesis ◽  
Underlying Mechanisms ◽  
Apoptotic Activity

Background: Colorectal cancer (CRC) is one of the most common causes of cancer-associated mortality in the world. Anti-tumor effect of curcumin has been shown in different cancers; however, the therapeutic potential of novel phytosomal curcumin, as well as the underlying molecular mechanism in CRC, has not yet been explored. Methods: The anti-proliferative, anti-migratory and apoptotic activity of phytosomal curcumin in CT26 cells was assessed by MTT assay, wound healing assay and Flow cytometry, respectively. Phytosomal curcumin was also tested for its in-vivo activity in a xenograft mouse model of CRC. In addition, oxidant/antioxidant activity was examined by DCFH-DA assay in vitro, measurement of malondialdehyde (MDA), Thiol and superoxidedismutase (SOD) and catalase (CAT) activity and also evaluation of expression levels of Nrf2 and GCLM by qRT-PCR in tumor tissues. In addition, the effect of phytosomal curcumin on angiogenesis was assessed by the measurement of VEGF-A and VEGFR-1 and VEGF signaling regulatory microRNAs (miRNAs) in tumor tissue. Results: Phytosomal curcumin exerts anti-proliferative, anti-migratory and apoptotic activity in-vitro. It also decreases tumor growth and augmented 5-fluorouracil (5-FU) anti-tumor effect in-vivo. In addition, our data showed that induction of oxidative stress and inhibition of angiogenesis through modulation of VEGF signaling regulatory miRNAs might be underlying mechanisms by which phytosomal curcumin exerted its antitumor effect. Conclusion: Our data confirmed this notion that phytosomal curcumin administrates anticancer effects and can be used as a complementary treatment in clinical settings.

scholarly journals Involvement of HECTD1 in LPS-induced astrocyte activation via σ-1R-JNK/p38-FOXJ2 axis

2021 ◽  
Vol 11 (1) ◽  
Author(s):  
Ying Tang ◽  
Mengchun Zhou ◽  
Rongrong Huang ◽  
Ling Shen ◽  
Li Yang ◽  
...  
Keyword(s):  
Inflammatory Responses ◽  
Astrocyte Activation ◽  
Hect Domain ◽  
P38 Inhibitor ◽  
Ubiquitin Protein Ligase ◽  
Primary Mouse ◽  
Lps Treatment

Abstract Background Astrocytes participate in innate inflammatory responses within the mammalian central nervous system (CNS). HECT domain E3 ubiquitin protein ligase 1 (HECTD1) functions during microglial activation, suggesting a connection with neuroinflammation. However, the potential role of HECTD1 in astrocytes remains largely unknown. Results Here, we demonstrated that HECTD1 was upregulated in primary mouse astrocytes after 100 ng/ml lipopolysaccharide (LPS) treatment. Genetic knockdown of HECTD1 in vitro or astrocyte-specific knockdown of HECTD1 in vivo suppressed LPS-induced astrocyte activation, whereas overexpression of HECTD1 in vitro facilitated LPS-induced astrocyte activation. Mechanistically, we established that LPS activated σ-1R-JNK/p38 pathway, and σ-1R antagonist BD1047, JNK inhibitor SP600125, or p38 inhibitor SB203580 reversed LPS-induced expression of HECTD1, thus restored LPS-induced astrocyte activation. In addition, FOXJ2 functioned as a transcription factor of HECTD1, and pretreatment of primary mouse astrocytes with BD1047, SB203580, and SP600125 significantly inhibited LPS-mediated translocation of FOXJ2 into the nucleus. Conclusions Overall, our present findings suggest that HECTD1 participates in LPS-induced astrocyte activation by activation of σ-1R-JNK/p38-FOXJ2 pathway and provide a potential therapeutic strategy for neuroinflammation induced by LPS or any other neuroinflammatory disorders.

scholarly journals Anticancer effects against colorectal cancer models of chloro(triethylphosphine)gold(I) encapsulated in PLGA–PEG nanoparticles

BioMetals ◽  
2021 ◽  
Author(s):  
Alessio Menconi ◽  
Tiziano Marzo ◽  
Lara Massai ◽  
Alessandro Pratesi ◽  
Mirko Severi ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
Gold Complex ◽  
Drug Candidate ◽  
Side Reactions ◽  
Anticancer Effects ◽  
Cancer Models ◽  
Free Gold ◽  
Hct 116 ◽  
New Formulation

AbstractChloro(triethylphosphine)gold(I), (Et3PAuCl hereafter), is an Auranofin (AF)-related compound showing very similar biological and pharmacological properties. Like AF, Et3PAuCl exhibits potent antiproliferative properties in vitro toward a variety of cancer cell lines and is a promising anticancer drug candidate. We wondered whether Et3PAuCl encapsulation might lead to an improved pharmacological profile also considering the likely reduction of unwanted side-reactions that are responsible for adverse effects and for drug inactivation. Et3PAuCl was encapsulated in biocompatible PLGA–PEG nanoparticles (NPs) and the new formulation evaluated in colorectal HCT-116 cancer cells in comparison to the free gold complex. Notably, encapsulated Et3PAuCl (nano-Et3PAuCl hereafter) mostly retains the cellular properties of the free gold complex and elicits even greater cytotoxic effects in colorectal cancer (CRC) cells, mediated by apoptosis and autophagy. Moreover, a remarkable inhibition of two crucial signaling pathways, i.e. ERK and AKT, by nano-Et3PAuCl, was clearly documented. The implications of these findings are discussed.

scholarly journals Anticancer effects of bifidobacteria on colon cancer cell lines

2021 ◽  
Vol 21 (1) ◽  
Author(s):  
Zeinab Faghfoori ◽  
Mohammad Hasan Faghfoori ◽  
Amir Saber ◽  
Azimeh Izadi ◽  
Ahmad Yari Khosroushahi
Keyword(s):  
Colorectal Cancer ◽  
Colon Cancer ◽  
Cancer Cells ◽  
Cell Lines ◽  
Cancer Cell ◽  
Colon Cancer Cell ◽  
Rt Pcr ◽  
Anticancer Effects ◽  
Colon Cancer Cell Lines ◽  
Apoptotic Genes

Abstract Background Colorectal cancer (CRC), with a growing incidence trend worldwide, is resistant to apoptosis and has uncontrolled proliferation. It is recently reported that probiotic microorganisms exert anticancer effects. The genus Bifidobacterium, one of the dominant bacterial populations in the gastrointestinal tract, has received increasing attention because of widespread interest in using it as health-promoting microorganisms. Therefore, the present study aimed to assess the apoptotic effects of some bifidobacteria species on colon cancer cell lines. Methods The cytotoxicity evaluations performed using MTT assay and FACS-flow cytometry tests. Also, the effects of five species of bifidobacteria secretion metabolites on the expression level of anti- or pro-apoptotic genes including BAD, Bcl-2, Caspase-3, Caspase-8, Caspase-9, and Fas-R studied by real-time polymerase chain reaction (RT-PCR) method. Results The cell-free supernatant of all studied bifidobacteria significantly decreased the survival rates of colon cancer cells compared with control groups. Flow cytometric and RT-PCR results indicated that apoptosis is induced by bifidobacteria secretion metabolites and the mechanism for the action of bifidobacteria species in CRC prevention could be down-regulation and up-regulation of anti-apoptotic and, pro-apoptotic genes. Conclusions In the present study, different bifidobacteria species showed anticancer activity on colorectal cancer cells through down-regulation and up-regulation of anti-apoptotic and pro-apoptotic genes. However, further studies are required to clarify the exact mechanism of apoptosis induction by bifidobacteria species.

scholarly journals Fucoxanthin and Colorectal Cancer Prevention

Cancers ◽  
2021 ◽  
Vol 13 (10) ◽  
pp. 2379
Author(s):  
Masaru Terasaki ◽  
Atsuhito Kubota ◽  
Hiroyuki Kojima ◽  
Hayato Maeda ◽  
Kazuo Miyashita ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
Brown Algae ◽  
Lifestyle Modification ◽  
Signal Pathways ◽  
Potential Candidate ◽  
Anticancer Effects ◽  
Cancer Models ◽  
Candidate Drug ◽  
Colorectal Cancer Prevention ◽  
Dietary Carotenoid

Colorectal cancer (CRC), which ranks among the top 10 most prevalent cancers, can obtain a good outcome with appropriate surgery and/or chemotherapy. However, the global numbers of both new cancer cases and death from CRC are expected to increase up to 2030. Diet-induced lifestyle modification is suggested to be effective in reducing the risk of human CRC; therefore, interventional studies using diets or diet-derived compounds have been conducted to explore the prevention of CRC. Fucoxanthin (Fx), a dietary carotenoid, is predominantly contained in edible brown algae, such as Undaria pinnatifida (wakame) and Himanthalia elongata (Sea spaghetti), which are consumed particularly frequently in Asian countries but also in some Western countries. Fx is responsible for a majority of the anticancer effects exerted by the lipophilic bioactive compounds in those algae. Interventional human trials have shown that Fx and brown algae mitigate certain risk factors for CRC; however, the direct mechanisms underlying the anti-CRC properties of Fx remain elusive. Fx and its deacetylated type “fucoxanthinol” (FxOH) have been reported to exert potential anticancer effects in preclinical cancer models through the suppression of many cancer-related signal pathways and the tumor microenvironment or alteration of the gut microbiota. We herein review the most recent studies on Fx as a potential candidate drug for CRC prevention.

scholarly journals Extract of Pogostemon cablin Possesses Potent Anticancer Activity against Colorectal Cancer Cells In Vitro and In Vivo

2020 ◽  
Vol 2020 ◽  
pp. 1-11 ◽  
Author(s):  
Ju-Huei Chien ◽  
Shan-Chih Lee ◽  
Kai-Fu Chang ◽  
Xiao-Fan Huang ◽  
Yi-Ting Chen ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
Cell Apoptosis ◽  
Cycle Arrest ◽  
Anticancer Effects ◽  
Pogostemon Cablin ◽  
Colorectal Cancer Cells ◽  
Potential Applicability ◽  
Cancer Suppression

Pogostemon cablin (PCa), an herb used in traditional Chinese medicine, is routinely used in the amelioration of different types of gastrointestinal discomfort. However, the mechanisms underlying the cancer suppression activity of PCa in colorectal cancer (CRC) cells have yet to be clarified. The aim of this study was to investigate the anticancer effects of PCa, specifically the induction of apoptosis in CRC cells. The growth inhibition curve of CRC cells following exposure to PCa was detected by an MTT assay. Moreover, PCa combined with 5-FU revealed a synergic effect of decreased cell viability. PCa inhibited cell proliferation and induced cell cycle arrest at the G0/G1 phase and cell apoptosis through regulation of associated protein expression. An in vivo study showed that PCa suppressed the growth of CRC via induction of cell apoptosis with no significant change in body weight or organ histology. Our results demonstrated that PCa inhibits the growth of CRC cells and induces apoptosis in vitro and in vivo, which suggests the potential applicability of PCa as an anticancer agent.

scholarly journals Means of self-preservation: how an intrinsically disordered ubiquitin-protein ligase averts self-destruction

2013 ◽  
Vol 24 (7) ◽  
pp. 1041-1052 ◽  
Author(s):  
Eric K. Fredrickson ◽  
Sarah V. Clowes Candadai ◽  
Cheuk Ho Tam ◽  
Richard G. Gardner
Keyword(s):  
Substrate Binding ◽  
Proteasomal Degradation ◽  
Ubiquitin Protein Ligase ◽  
Intrinsically Disordered ◽  
Ubiquitin Conjugating Enzyme ◽  
In Trans ◽  
Key Residues ◽  
In Cis ◽  
Self Protection ◽  
Disordered Regions

Ubiquitin-protein ligases (E3s) that ubiquitinate substrates for proteasomal degradation are often in the position of ubiquitinating themselves due to interactions with a charged ubiquitin-conjugating enzyme (E2). This can mediate the E3’s proteasomal degradation. Many E3s have evolved means to avoid autoubiquitination, including protection by partner or substrate binding, preventative modifications, and deubiquitinating enzyme reversal of ubiquitination. Here we describe another adaptation for E3 self-protection discovered while exploring San1, which ubiquitinates misfolded nuclear proteins in yeast for proteasomal degradation. San1 is highly disordered in its substrate-binding regions N- and C-terminal to its RING domain. In cis autoubiquitination could occur if these flexible regions come in proximity to the E2. San1 prevents this by containing no lysines in its disordered regions; thus the canonical residue used for ubiquitin attachment has been selectively eliminated. San1’s target substrates have lost their native structures and expose hydrophobicity. To avoid in trans autoubiquitination, San1 possesses little concentrated hydrophobicity in its disordered regions, and thus the that feature San1 recognizes in misfolded substrates has also been selectively eliminated. Overall the presence of key residues in San1 have been evolutionarily minimized to avoid self-destruction either in cis or in trans. Our work expands the ways in which E3s protect themselves from autoubiquitination.

Biochemical assessment of the neurotoxicity of gold nanoparticles functionalized with colorectal cancer-targeting peptides in a rat model

2021 ◽  
pp. 096032712110176
Author(s):  
MC Pereira ◽  
OB Adewale ◽  
S Roux ◽  
L Cairncross ◽  
H Davids
Keyword(s):  
Oxidative Stress ◽  
Colorectal Cancer ◽  
Brain Tissue ◽  
Tumour Necrosis ◽  
Cancer Targeting ◽  
Tumour Necrosis Factor Α ◽  
Peptide Conjugates ◽  
Factor Α ◽  
Apoptotic Effects ◽  
Necrosis Factor

The application of gold nanoparticle-peptide conjugates as theranostic agents for colorectal cancer shows much promise. This study aimed at determining the neurotoxic impact of 14 nm gold nanoparticles (AuNPs) functionalized with colorectal cancer-targeting peptides (namely p.C, p.L or p.14) in a rat model. Brain tissue samples, obtained from Wistar rats that received a single injection of citrate-capped AuNPs, polyethylene glycol-coated (PEG) AuNPs, p.C-PEG-AuNPs, p.L-PEG-AuNPs or p.14-PEG-AuNPs, and sacrificed after 2- and 12-weeks, respectively, were analysed. Inflammation marker (tumour necrosis factor-α, interleukin-6, interleukin-1β), oxidative stress (superoxide dismutase, catalase, glutathione peroxidase) and apoptotic biomarker (cytochrome c, caspase-3) levels were measured. Gold nanoparticle-treated groups sacrificed after 2-weeks did not exhibit any significant inflammatory, oxidative stress or apoptotic effects in brain tissue compared to the untreated control group. In brain tissue from rats that were exposed to citrate-capped AuNPs for 12-weeks, tumour necrosis factor-α and interleukin-6 levels were significantly increased compared to the untreated control. Exposure to PEG-AuNP, p.C-PEG-AuNP, p.L-PEG-AuNP and p.14-PEG-AuNP did not elicit significant toxic effects compared to the control after 12-weeks, as evidenced by the absence of inflammatory, oxidative stress and apoptotic effects in brain tissue. We thus report on the safety of PEG-coated AuNP-peptide conjugates for potential application in the diagnosis of colorectal cancer; however, exposure to citrate-capped AuNPs could induce delayed neuro-inflammation, and as such, warrants further investigation.

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