Details of a Researcher - Soga, Tomoyoshi

Papers - Soga, Tomoyoshi

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SETD1A regulates transcriptional pause release of heme biosynthesis genes in leukemia

Hoshii, T., Perlee, S., Kikuchi, S., Rahmutulla, B, Fukuyo, M., Masuda, T., Ohtsuki, S., Soga, T., Nabet, B., Kaneda, A.

Cell Rep. 41 ( 9 ) 111727 2022.11

Research paper (scientific journal), Joint Work, Accepted

Histone methyltransferase SETD1A is critical for acute myeloid leukemia (AML) cell survival, but the molecular mechanism driving SETD1A gene regulation remains elusive. To delineate the role of SETD1A, we utilize a protein degrader technology to induce rapid SETD1A degradation in AML cell lines. SETD1A degradation results in immediate downregulation of transcripts associated with DNA repair and heme biosynthesis pathways. CRISPR-based functional analyses and metabolomics reveal an essential role of SETD1A to maintain mitochondrial respiration in AML cells. These SETD1A targets are enriched in head-to-head (H2H) genes. SETD1A degradation disrupts a non-enzymatic SETD1A domain-dependent cyclin K function, increases the Ser5P RNA polymerase II (RNAPII) at the transcriptional start site (TSS), and induces the promoter-proximal pausing of RNAPII in a strand-specific manner. This study reveals a non-enzymatic role for SETD1A in transcriptional pause release and provides insight into the mechanism of RNAPII pausing and its function in cancer.

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Relationship between [18 F]FDG PET/CT and metabolomics in patients with colorectal cancer

Imajo, M., Norikane, T., Yamamoto, Y., Maeda, Y., Saitoh, K., Kato, K., Soga, T., Okano, K., Nishiyama, Y.

Metabolomics 18 ( 11 ) 91 2022.11

Research paper (scientific journal), Joint Work, Accepted

Introduction: Advances in metabolomics have significantly improved cancer detection, diagnosis, treatment, and prognosis.

Objectives: To investigate the relationship between metabolic tumor volume (MTV) using 2-deoxy-2-[18F]fluoro-D-glucose (FDG) positron emission tomography (PET)/ computed tomography (CT) and metabolomics data in patients with colorectal cancer (CRC).

Methods: The metabolome in tumor tissues was analyzed using capillary electrophoresis time-of-flight mass spectrometry in 33 patients with newly diagnosed CRC who underwent FDG PET/CT before treatment and had tumor tissue post-surgery. Based on the FDG PET data, MTV was calculated and was dichotomized according to the median value, and tumors were divided into low-MTV and high-MTV tumors. Metabolomics data were compared between the low-MTV and high-MTV tumors.

Results: The levels of most glycolysis-related metabolites were not different between low-MTV and high-MTV tumors. The level of component of the initial part of the tricarboxylic acid (TCA) cycle, citrate, was significantly lower in the high-MTV tumor than in the low-MTV tumor. The TCA intermediate succinate level was significantly higher in the high-MTV tumor than in the low-MTV tumor. In contrast, the TCA intermediate fumarate level was significantly lower in the high-MTV tumor than in the low-MTV tumor. The levels of many amino acids were significantly higher in the high-MTV tumor than in the low-MTV tumor.

Conclusions: Although preliminary, these results suggest that tumors with high FDG metabolism in CRC may obtain more energy by using a reverse reaction of the TCA cycle and amino-acid metabolism. However, further research is required to clarify this relationship.

Keywords: Colorectal cancer; FDG; Metabolome; PET/CT.

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Comprehensive metabolome analysis of intracellular metabolites in cultured cells

Kudo, R., Igarashi, K., Soga, T., Ishikawa, T., Saito, Y.

STAR Protoc. 3 ( 3 ) 101531 2022.09

Research paper (scientific journal), Joint Work, Accepted

Capillary electrophoresis mass spectrometry (CE-MS) can measure the intracellular amount of highly polar and charged metabolites; liquid chromatography mass spectrometry (LC-MS) can quantify hydrophobic metabolites. A comprehensive metabolome analysis requires independent sample preparation for LC-MS and CE-MS. Here, we present a protocol to prepare for sequentially analyzing the metabolites from one sample. Here we describe the steps for breast cancer cell lines, MCF-7 cells, but the protocol can be applied to other cell types.

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Development of Fluorophosphoramidate as a Biocompatibly Transformable Functional Group and its Application as a Phosphate Prodrug for Nucleoside Analogs

Yoshida, Y., Zheng, T., Tanabe, W., Tomoike, F., Hashiya, F., Suzuki, T., Hirota, S., Saiki, Y., Horii, A., Hirayama, A., Soga, T., Kimura, Y., Abe, H.

ChemMedChem 17 ( 17 ) e202200188 2022.09

Research paper (scientific journal), Joint Work, Accepted

Synthetic phosphate-derived functional groups are important for controlling the function of bioactive molecules in vivo. Herein we describe the development of a new type of biocompatible phosphate analog, a fluorophosphoramidate (FPA) functional group that has characteristic P-F and P-N bonds. We found that FPA with a primary amino group was relatively unstable in aqueous solution and was converted to a monophosphate, while FPA with a secondary amino group was stable. Furthermore, by improving the molecular design of FPA, we developed a reaction in which a secondary amino group is converted to a primary amino group in the intracellular environment and clarified that the FPA group functions as a phosphate prodrug of nucleoside. Various FPA-gemcitabine derivatives were synthesized and their toxicity to cancer cells were evaluated. One of the FPA-gemcitabine derivatives showed superior toxicity compared with gemcitabine and its ProTide prodrug, which methodology is widely used in various nucleoside analogs, including anti-cancer and anti-virus drugs.

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Brown adipose tissue dysfunction promotes heart failure via a trimethylamine N-oxide-dependent mechanism

Yoshida, Y., Shimizu, I., Shimada, A., Nakahara, K., Yanagisawa, S., Kubo, M., Fukuda, S., Ishii, C., Yamamoto, H., Ishikawa, T., Kano, K., Aoki, J., Katsuumi, G., Suda, M., Ozaki, K., Yoshida, Y., Okuda, S., Ohta, S., Okamoto, S., Minokoshi, Y., Oda, K., Sasaoka, T., Abe, M., Sakimura, K., Kubota, Y., Yoshimura, N., Kajimura, S., Zuriaga, M., Walsh, K., Soga, T., Minamino, T.

Sci. Rep. 12 14883 2022.09

Research paper (scientific journal), Joint Work, Accepted

Low body temperature predicts a poor outcome in patients with heart failure, but the underlying pathological mechanisms and implications are largely unknown. Brown adipose tissue (BAT) was initially characterised as a thermogenic organ, and recent studies have suggested it plays a crucial role in maintaining systemic metabolic health. While these reports suggest a potential link between BAT and heart failure, the potential role of BAT dysfunction in heart failure has not been investigated. Here, we demonstrate that alteration of BAT function contributes to development of heart failure through disorientation in choline metabolism. Thoracic aortic constriction (TAC) or myocardial infarction (MI) reduced the thermogenic capacity of BAT in mice, leading to significant reduction of body temperature with cold exposure. BAT became hypoxic with TAC or MI, and hypoxic stress induced apoptosis of brown adipocytes. Enhancement of BAT function improved thermogenesis and cardiac function in TAC mice. Conversely, systolic function was impaired in a mouse model of genetic BAT dysfunction, in association with a low survival rate after TAC. Metabolomic analysis showed that reduced BAT thermogenesis was associated with elevation of plasma trimethylamine N-oxide (TMAO) levels. Administration of TMAO to mice led to significant reduction of phosphocreatine and ATP levels in cardiac tissue via suppression of mitochondrial complex IV activity. Genetic or pharmacological inhibition of flavin-containing monooxygenase reduced the plasma TMAO level in mice, and improved cardiac dysfunction in animals with left ventricular pressure overload. In patients with dilated cardiomyopathy, body temperature was low along with elevation of plasma choline and TMAO levels. These results suggest that maintenance of BAT homeostasis and reducing TMAO production could be potential next-generation therapies for heart failure.

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Salivary metabolomics with machine learning for colorectal cancer detection

Kuwabara, H., Katsumata, K., Iwabuthi, A., Udo, R., Tago, T., Kasahara, K., Mazaki, J., Enomoto, M., Ishizaki, T., Soya, R., Kaneko, M., Ota, S., Enomoto, A., Soga, T., Tomita, M., Sunamura, M., Tsuchida, A., Sugimoto, M., Nagakawa, Y.

Cancer Sci. 113 ( 9 ) 3234 - 3243 2022.09

Research paper (scientific journal), Joint Work, Accepted

As the worldwide prevalence of colorectal cancer (CRC) increases, it is vital to reduce its morbidity and mortality through early detection. Saliva-based tests are an ideal noninvasive tool for CRC detection. Here, we explored and validated salivary biomarkers to distinguish patients with CRC from those with adenoma (AD) and healthy controls (HC). Saliva samples were collected from patients with CRC, AD, and HC. Untargeted salivary hydrophilic metabolite profiling was conducted using capillary electrophoresis–mass spectrometry and liquid chromatography–mass spectrometry. An alternative decision tree (ADTree)-based machine learning (ML) method was used to assess the discrimination abilities of the quantified metabolites. A total of 2,602 unstimulated saliva samples were collected from subjects with CRC (n = 231), AD (n = 54), and HC (n = 2,317). Data were randomly divided into training (n = 1,301) and validation datasets (n = 1,301). The clustering analysis showed a clear consistency of aberrant metabolites between the two groups. The ADTree model was optimized through cross-validation (CV) using the training dataset, and the developed model was validated using the validation dataset. The model discriminating CRC + AD from HC showed area under the receiver operating characteristic curves (AUC) of 0.860 (95% confidence interval [CI]: 0.828-0.891) for CV and 0.870 (95% CI: 0.837-0.903) for the validation dataset. The other model discriminating CRC from AD + HC showed an AUC of 0.879 (95% CI: 0.851-0.907) and 0.870 (95% CI: 0.838 - 0.902), respectively. Salivary metabolomics combined with ML demonstrated high accuracy and versatility in detecting CRC.

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In vivo transomic analyses of glucose-responsive metabolism in skeletal muscle reveal core differences between the healthy and obese states

Kokaji, T., Eto, M., Hatano, A., Yugi K., Morita, K., Ohno, S., Fujii, M., Hironaka, K., Ito, Y., Egami, R., Uematsu, S., Terakawa, A., Pan, Y., Maehara, H., Li, D., Bai, Y., Tsuchiya, T., Ozaki, H., Inoue, H., Kubota, H., Suzuki, Y., Hirayama, A., Soga, T., Kuroda, S.

Sci. Rep. 12 13719 2022.08

Research paper (scientific journal), Joint Work, Accepted

Metabolic regulation in skeletal muscle is essential for blood glucose homeostasis. Obesity causes insulin resistance in skeletal muscle, leading to hyperglycemia and type 2 diabetes. In this study, we performed multiomic analysis of the skeletal muscle of wild-type (WT) and leptin-deficient obese (ob/ob) mice, and constructed regulatory transomic networks for metabolism after oral glucose administration. Our network revealed that metabolic regulation by glucose-responsive metabolites had a major effect on WT mice, especially carbohydrate metabolic pathways. By contrast, in ob/ob mice, much of the metabolic regulation by glucose-responsive metabolites was lost and metabolic regulation by glucose-responsive genes was largely increased, especially in carbohydrate and lipid metabolic pathways. We present some characteristic metabolic regulatory pathways found in central carbon, branched amino acids, and ketone body metabolism. Our transomic analysis will provide insights into how skeletal muscle responds to changes in blood glucose and how it fails to respond in obesity.

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Tumor metabolic alterations after neoadjuvant chemoradiotherapy predict postoperative recurrence in patients with pancreatic cancer

Wada, Y., Okano, K., Sato, K., Sugimoto, M., Shimomura, A., Nagao, M., Matsukawa, H., Ando, Y., Suto, H., Oshima, M., Kondo, A., Asano, E., Kishino, T., Kumamoto, K., Kobara, H., Kamada, H., Masaki, T., Soga, T., Suzuki, Y.

Jpn J Clin Oncol. 52 ( 8 ) 879 - 887 2022.08

Research paper (scientific journal), Joint Work, Accepted

Objective: We investigated the metabolic changes in pancreatic ductal adenocarcinoma to identify the mechanisms of treatment response of neoadjuvant chemoradiation therapy.

Methods: Frozen tumor and non-neoplastic pancreas tissues were prospectively obtained from 88 patients with pancreatic ductal adenocarcinoma who underwent curative-intent surgery. Sixty-two patients received neoadjuvant chemoradiation therapy and 26 patients did not receive neoadjuvant therapy (control group). Comprehensive analysis of metabolites in tumor and non-neoplastic pancreatic tissue was performed by capillary electrophoresis-mass spectrometry.

Results: Capillary electrophoresis-mass spectrometry detected 90 metabolites for analysis among more than 500 ionic metabolites quantified. There were significant differences in 27 tumor metabolites between the neoadjuvant chemoradiation therapy and control groups. There were significant differences in eight metabolites [1-MethylnNicotinamide, Carnitine, Glucose, Glutathione (red), N-acetylglucosamine 6-phosphate, N-acetylglucosamine 1-phosphate, UMP, Phosphocholine] between good responder and poor responder for neoadjuvant chemoradiation therapy. Among these metabolites, phosphocholine, Carnitine and Glutathione were associated with recurrence-free survival only in the neoadjuvant chemoradiation therapy group. Microarray confirmed marked gene suppression of choline transporters [CTL1-4 (SLC44A1-44A4)] in pancreatic ductal adenocarcinoma tissue of neoadjuvant chemoradiation therapy group.

Conclusion: The present study identifies several important metabolic consequences and potential neoadjuvant chemoradiation therapy targets in pancreatic ductal adenocarcinoma. Choline metabolism is one of the key pathways involved in recurrence of the patients with pancreatic ductal adenocarcinoma who received neoadjuvant chemoradiation therapy.

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Glutamine deficiency in solid tumor cells confers resistance to ribosomal RNA synthesis inhibitors

Pan, M., Zorbas, C., Sugaya, M., Ishiguro, K., Kato, M., Nishida, M., Zhang, H.F., Candeias, M.M., Okamoto, A., Ishikawa, T., Soga, T., Aburatani, H., Sakai, J., Matsumura, Y., Suzuki, T., Proud, C.G., Lafontaine, D.L.J., Osawa, T.

Nat Commun. 13 ( 1 ) 3706 2022.06

Research paper (scientific journal), Joint Work, Accepted

Ribosome biogenesis is an energetically expensive program that is dictated by nutrient availability. Here we report that nutrient deprivation severely impairs precursor ribosomal RNA (pre-rRNA) processing and leads to the accumulation of unprocessed rRNAs. Upon nutrient restoration, pre-rRNAs stored under starvation are processed into mature rRNAs that are utilized for ribosome biogenesis. Failure to accumulate pre-rRNAs under nutrient stress leads to perturbed ribosome assembly upon nutrient restoration and subsequent apoptosis via uL5/uL18-mediated activation of p53. Restoration of glutamine alone activates p53 by triggering uL5/uL18 translation. Induction of uL5/uL18 protein synthesis by glutamine is dependent on the translation factor eukaryotic elongation factor 2 (eEF2), which is in turn dependent on Raf/MEK/ERK signaling. Depriving cells of glutamine prevents the activation of p53 by rRNA synthesis inhibitors. Our data reveals a mechanism that tumor cells can exploit to suppress p53-mediated apoptosis during fluctuations in environmental nutrient availability.

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Comparative Metabolomics of Small Molecules Specifically Expressed in the Dorsal or Ventral Marginal Zones in Vertebrate Gastrula

Suzuki, Y., Hayasaka, R., Hasebe, M., Ikeda, S., Soga, T., Tomita, M., Hirayama, A., Kuroda, H.

Metabolites 12 ( 6 ) 566 2022.06

Research paper (scientific journal), Joint Work, Accepted

Many previous studies have reported the various proteins specifically secreted as inducers in the dorsal or ventral regions in vertebrate gastrula. However, little is known about the effect on cell fate of small molecules below 1000 Da. We therefore tried to identify small molecules specifically expressed in the dorsal marginal zone (DMZ) or ventral marginal zone (VMZ) in vertebrate gastrula. Small intracellular and secreted molecules were detected using explants and supernatant samples. Hydrophilic metabolites were analyzed by capillary ion chromatography–mass spectrometry and liquid chromatography–mass spectrometry, and lipids were analyzed by supercritical fluid chromatography–tandem mass spectrometry. In total, 190 hydrophilic metabolites and 396 lipids were identified. The DMZ was found to have high amounts of glycolysis- and glutathione metabolism-related metabolites in explants, and the VMZ was richer in purine metabolism-related metabolites. We also discovered some hydrophilic metabolites and lipids differentially contained in the DMZ or VMZ. Our research would contribute to a deeper understanding of the cellular physiology that regulates early embryogenesis.

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AGE/RAGE axis regulates reversible transition to quiescent states of ALK-rearranged NSCLC and pancreatic cancer cells in monolayer cultures

Kadonosono, T., Miyamoto, K., Sasaki, S., Matsuo, Y., Kitajima, S., Wang, Q., Endo, M., Nibori, M., Kuchimaru, T., Soga, T., Hirota, K., Kizaka-Kondoh, S.

Sci. Rep. 12 9886 2022.06

Research paper (scientific journal), Joint Work, Accepted

Cancer recurrence due to tumor cell quiescence after therapy and long-term remission is associated with cancer-related death. Previous studies have used cell models that are unable to return to a proliferative state; thus, the transition between quiescent and proliferative states is not well understood. Here, we report monolayer cancer cell models wherein the human non-small cell lung carcinoma cell line H2228 and pancreatic cancer cell line AsPC-1 can be reversibly induced to a quiescent state under hypoxic and serum-starved (HSS) conditions. Transcriptome and metabolome dual-omics profiles of these cells were compared with those of the human lung adenocarcinoma cell line A549, which was unable to enter a quiescent state under HSS conditions. The quiescence-inducible cells had substantially lower intracellular pyruvate and ATP levels in the quiescent state than in the proliferative state, and their response to sudden demand for energy was dramatically reduced. Furthermore, in quiescence-inducible cells, the transition between quiescent and proliferative states of these cells was regulated by the balance between the proliferation-promoting Ras and Rap1 signaling and the suppressive AGE/RAGE signaling. These cell models elucidate the transition between quiescent and proliferative states, allowing the development of drug-screening systems for quiescent tumor cells.

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Different types of reactions to E7386 among colorectal cancer patient-derived organoids and corresponding CAFs

Imai, T., Naruse, M., Ochiai M., Matsumoto K., Ikeda S., Kani, M., Kato, Y., Hirayama, A., Soga, T., Hori, Y., Yokoi, A., Ochiai, A.

Oncol. Lett. 24 ( 1 ) 221 2022.05

Research paper (scientific journal), Joint Work, Accepted

Colorectal cancer (CRC) harbors genetic alterations in a component of the Wnt signaling pathway in ~90% of cases. In addition, the Wnt signaling pathway has been previously suggested to serve a notable role in the pathophysiology of CRC cells and cancer‑associated fibroblasts (CAFs). In the present study, the possible effects of E7386, a selective inhibitor of the interaction between β‑catenin and the cAMP response element‑binding protein‑binding protein, were evaluated using organoids and the corresponding CAFs derived from patients with CRC. E7386 at 100 nM was revealed to decrease the viability of CRC organoids and CAFs. Analysis of the gene expression profiles revealed marked changes in the expression levels of different types of cancer‑associated genes associated with E7386 concentrations in the organoids and/or CAFs, such as those regulating glucose and amino acid metabolism [phosphoenolpyruvate carboxykinase 2, asparagine synthetase (glutamine‑hydrolyzing), phosphoserine aminotransferase 1 and phosphoglycerate dehydrogenase], stimulation of natural killer cell‑mediated cytotoxicity (UL16‑binding protein 1) and modification of the Wnt/β‑catenin signaling pathway (indicated by very low density lipoprotein receptor). Results of the hydrophilic metabolome analysis in the organoids were consistent with those of the transcriptomic analysis. In vivo experiments used corresponding xenograft models, although changes in volume of tumor tissues could not be observed at 50 mg/kg body weight twice a day for 14 days, results on the protein expression levels partially supported those in the in vitro experiments. In conclusion, different types of reactions, such as alterations in the glucose and amino acid metabolic pathways, stimulation of stress responses and NK‑cell mediated cytotoxicity and components in the Wnt/β‑catenin signaling pathway, to E7386 in the CRC organoids and corresponding CAFs were observed under conditions with decreased cell viability. However, further mechanistic studies to clarify the relationships with Wnt/β‑catenin signaling pathway and these reactions using preclinical models and biomarker studies using clinical human samples are required for verification of the present preclinical biomarkers.

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Differing impact of phosphoglycerate mutase 1-deficiency on brown and white adipose tissue

Yoshida, Y., Shimizu, I., Hsiao, Y.T., Suda, M., Katsuumi, G., Seki, M., Suzuki, Y., Okuda, S., Soga, T., Minamino, T.

iScience 25 ( 5 ) 104268 2022.05

Research paper (scientific journal), Joint Work, Accepted

Brown adipose tissue (BAT) is a metabolically active organ that contributes to the thermogenic response to cold exposure. In addition, other thermogenic cells termed beige adipocytes are generated in white adipose tissue (WAT) by cold exposure. Although activation of brown/beige adipose tissue is associated with mobilization of both glucose and lipids, few studies have focused on the role of glycolytic enzymes in regulating adipose tissue function. We generated mouse models with specific deletion of the glycolytic enzyme phosphoglycerate mutase 1 (PGAM1) from adipose tissue. Deletion of Pgam1 from both BAT and WAT promoted whitening of BAT with beiging of visceral WAT, whereas deletion of Pgam1 from BAT alone led to whitening of BAT without beiging of WAT. Our results demonstrate a potential role of glycolytic enzymes in beiging of visceral WAT and suggest that PGAM1 would be a novel therapeutic target in obesity and diabetes.

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Polarity protein SCRIB interacts with SLC3A2 to regulate proliferation and tamoxifen resistance in ER+ breast cancer

Saito, Y., Matsuda, S., Ohnishi, N., Endo, K., Ashitani, S., Ohishi, M., Ueno, A., Tomita, M., Ueda, K., *Soga, T., *Muthuswamy, S.K

Commun. Biol. 5 ( 1 ) 403 2022.05

Research paper (scientific journal), Joint Work, Accepted

Estrogen receptor (ER) positive breast cancer represents 75% of all breast cancers in women. Although patients with ER+ cancers receive endocrine therapies, more than 30% develop resistance and succumb to the disease, highlighting the need to understand endocrine resistance. Here we show an unexpected role for the cell polarity protein SCRIB as a tumor-promoter and a regulator of endocrine resistance in ER-positive breast cancer cells. SCRIB expression is induced by estrogen signaling in a MYC-dependent manner. SCRIB interacts with SLC3A2, a heteromeric component of leucine amino acid transporter SLC7A5. SLC3A2 binds to the N-terminus of SCRIB to facilitate the formation of SCRIB/SLC3A2/LLGL2/SLC7A5 quaternary complex required for membrane localization of the amino acid transporter complex. Both SCRIB and SLC3A2 are required for cell proliferation and tamoxifen resistance in ER+ cells identifying a new role for the SCRIB/SLC3A2 complex in ER+ breast cancer.

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S-adenosyl-L-homocysteine extends lifespan through methionine restriction effects

Ogawa, T., Masumura, K., Kohara, Y., Kanai, M., Soga, T., Ohya, Y., Blackwell, T.K. Mizunuma, M.

Aging Cell 21 ( 5 ) e13604 2022.05

Research paper (scientific journal), Joint Work, Accepted

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Surgical Treatment for Colorectal Cancer Partially Restores Gut Microbiome and Metabolome Traits

Shiroma, H., Shiba, S., Erawijantari, P.P., Takamaru, H., Yamada, M., Sakamoto, T., Kanemitsu, Y., Mizutani, S., Soga, T., Saito, Y., Shibata, T., Fukuda, S., Yachida, S., Yamada, T.

mSystems 7 ( 2 ) e0001822 2022.04

Research paper (scientific journal), Joint Work, Accepted

Accumulating evidence indicates that the gut microbiome and metabolites are associated with colorectal cancer (CRC). However, the influence of surgery for CRC treatment on the gut microbiome and metabolites and how it relates to CRC risk in postoperative CRC patients remain partially understood. Here, we collected 170 fecal samples from 85 CRC patients pre- and approximately 1 year postsurgery and performed shotgun metagenomic sequencing and capillary electrophoresis-time of flight mass spectrometry-based metabolomics analyses to characterize alterations between pre- and postsurgery. We determined that the relative abundance of 114 species was altered postsurgery (P < 0.005). CRC-associated species, such as Fusobacterium nucleatum, were decreased postsurgery. On the other hand, Clostridium scindens, carcinogenesis-associated deoxycholate (DCA)-producing species, and its biotransformed genes (bai operon) were increased postsurgery. The concentration of 60 fecal metabolites was also altered postsurgery (P < 0.005). Two bile acids, cholate and DCA, were increased postsurgery. We developed methods to estimate postoperative CRC risk based on the gut microbiome and metabolomic compositions using a random forest machine-learning algorithm that classifies large adenoma or early-stage CRC and healthy controls from publicly available data sets. We applied methods to preoperative samples and then compared the estimated CRC risk between the two groups according to the presence of large adenoma or tumors 5 years postsurgery (P < 0.05). Overall, our results show that the gut microbiome and metabolites dynamically change from pre- to postsurgery. In postoperative CRC patients, potential CRC risk derived from gut microbiome and metabolites still remains, which indicates the importance of follow-up assessments. IMPORTANCE The gut microbiome and metabolites are associated with CRC progression and carcinogenesis. Postoperative CRC patients are reported to be at an increased CRC risk; however, how gut microbiome and metabolites are related to CRC risk in postoperative patients remains only partially understood. In this study, we investigated the influence of surgical CRC treatment on the gut microbiome and metabolites. We found that the CRC-associated species Fusobacterium nucleatum was decreased postsurgery, whereas carcinogenesis-associated DCA and its producing species and genes were increased postsurgery. We developed methods to estimate postoperative CRC risk based on the gut microbiome and metabolomic compositions. We applied methods to compare the estimated CRC risk between two groups according to the presence of large adenoma or tumors after 5 years postsurgery. To our knowledge, this study is the first report on differences between pre- and postsurgery using metagenomics and metabolomics data analysis. Our methods might be used for CRC risk assessment in postoperative patients.

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Plant hvu-MIR168-3p enhances expression of glucose transporter 1 (SLC2A1) in human cells by silencing genes related to mitochondrial electron transport chain complex I

Akao, Y., Kuranaga, Y., Heishima, K., Sugito, N., Morikawa, K., Ito, Y., Soga, T., Ito, T.

J. Nutr. Biochem. 101 108922 2022.03

Research paper (scientific journal), Joint Work, Accepted, ISSN 09552863

Diet is a crucial factor for preventing most diseases. Edible plant extracts are known to contain exosome-like nanoparticles, in which food-derived plant microRNAs are included and may serve as a novel functional component in human health. Here, we demonstrated that hvu-MIR168-3p included in the nanoparticles of rice aleurone cells down-regulated the expression of the genes related to mitochondrial electron transport chain complex I in human cells. Subsequently, hvu-MIR168-3p enhanced protein and RNA expression levels of glucose transporter I and caused a decrease in the blood glucose level, which findings were obtained by in vitro and in vivo experiments, respectively. These findings suggest that a cross-kingdom relationship between plants and humans with respect to hvu-MIR168-3p exists and may contribute to preventive medicine for GLUT1-related dysfunctions including glucose metabolism, aging, and tumor immunology.

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Metabolic profiling of prostate cancer in skeletal microenvironments identifies G6PD as a key mediator of growth and survival

Whitburn, J., Rao, S.R., Morris, E.V., Tabata, S., Hirayama, A., Soga, T., Edwards, J.R., Kaya, Z., Palmer, C., Hamdy, F.C., Edwards, C.M.

Sci. Adv. 8 ( 8 ) eabf9096 2022.02

Research paper (scientific journal), Joint Work, Accepted

The spread of cancer to bone is invariably fatal, with complex cross-talk between tumor cells and the bone microenvironment responsible for driving disease progression. By combining in silico analysis of patient datasets with metabolomic profiling of prostate cancer cells cultured with bone cells, we demonstrate the changing energy requirements of prostate cancer cells in the bone microenvironment, identifying the pentose phosphate pathway (PPP) as elevated in prostate cancer bone metastasis, with increased expression of the PPP rate-limiting enzyme glucose-6-phosphate dehydrogenase (G6PD) associated with a reduction in progression-free survival. Genetic and pharmacologic manipulation demonstrates that G6PD inhibition reduces prostate cancer growth and migration, associated with changes in cellular redox state and increased chemosensitivity. Genetic blockade of G6PD in vivo results in reduction of tumor growth within bone. In summary, we demonstrate the metabolic plasticity of prostate cancer cells in the bone microenvironment, identifying the PPP and G6PD as metabolic targets for the treatment of prostate cancer bone metastasis.

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Multi-omics-based label-free metabolic flux inference reveals obesity-associated dysregulatory mechanisms in liver glucose metabolism

Uematsu, S., Ohno, S., Tanaka, K.Y., Hatano, A., Kokaji, T., Ito, Y., Kubota, H., Hironaka, K., Suzuki, Y., Matsumoto, M., Nakayama, K.I., Hirayama, A., Soga, T., Kuroda, S.

iScience 25 ( 2 ) 103787 2022.02

Research paper (scientific journal), Joint Work, Accepted

Glucose homeostasis is maintained by modulation of metabolic flux. Enzymes and metabolites regulate the involved metabolic pathways. Dysregulation of glucose homeostasis is a pathological event in obesity. Analyzing metabolic pathways and the mechanisms contributing to obesity-associated dysregulation in vivo is challenging. Here, we introduce OMELET: Omics-Based Metabolic Flux Estimation without Labeling for Extended Trans-omic Analysis. OMELET uses metabolomic, proteomic, and transcriptomic data to identify relative changes in metabolic flux, and to calculate contributions of metabolites, enzymes, and transcripts to the changes in metabolic flux. By evaluating the livers of fasting ob/ob mice, we found that increased metabolic flux through gluconeogenesis resulted primarily from increased transcripts, whereas that through the pyruvate cycle resulted from both increased transcripts and changes in substrates of metabolic enzymes. With OMELET, we identified mechanisms underlying the obesity-associated dysregulation of metabolic flux in the liver.

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Four features of temporal patterns characterize similarity among individuals and molecules by glucose ingestion in humans

Fujita, S., Karasawa, Y., Fujii, M., Hironaka, K., Uda, S., Kubota, H., Inoue, H., Sumitomo, Y., Hirayama, A., Soga, T., Kuroda, S.

NPJ Syst. Biol. Appl. 8 ( 1 ) 6 2022.02

Research paper (scientific journal), Joint Work, Accepted

Oral glucose ingestion induces systemic changes of many blood metabolites related not only to glucose, but also other metabolites such as amino acids and lipids through many blood hormones. However, the detailed temporal changes in the concentrations of comprehensive metabolites and hormones over a long time by oral glucose ingestion are uncharacterized. We measured 83 metabolites and 7 hormones in 20 healthy human subjects in response to glucose ingestion. We characterized temporal patterns of blood molecules by four features: (i) the decomposability into "amplitude" and "rate" components, (ii) the similarity of temporal patterns among individuals, (iii) the relation of molecules over time among individuals, and (iv) the similarity of temporal patterns among molecules. Glucose and glucose metabolism-related hormones indicated a rapid increase, and citrulline and lipids, which indicated a rapid decrease, returned to fasting levels faster than amino acids. Compared to glucose metabolism-related molecules and lipids, amino acids showed similar temporal patterns among individuals. The four features of temporal patterns of blood molecules by oral glucose ingestion characterize the differences among individuals and among molecules.

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