Details of a Researcher - Soga, Tomoyoshi

Papers - Soga, Tomoyoshi

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Characterization of cancer omics and drug perturbations in panels of lung cancer cells

Suzuki, A., Onodera, K., Matsui, K., Seki, M., Esumi, H., Soga, T., Sugano, S., Kohno, T., Suzuki, Y., Tsuchihara, K.

Sci Rep 9 ( 1 ) 19529 2019.12

Research paper (scientific journal), Joint Work, Accepted

To better understand the disruptions of transcriptional regulations and gene expression in lung cancers, we constructed a multi-omics catalogue of the responses of lung cancer cells to a series of chemical compounds. We generated and analyzed 3,240 RNA-seq and 3,393 ATAC-seq libraries obtained from 23 cell lines treated with 95 well-annotated compounds. To demonstrate the power of the created multi-omics resource, we attempted to identify drugs that could induce the designated changes alone or in combination. The basal multi-omics information was first integrated into co-expression modules. Among these modules, we identified a stress response module that may be a promising drug intervention target, as new combinations of compounds that could be used to regulate this module and the consequent phenotypic appearance of cancer cells have been identified. We believe that the multi-omics profiles generated in this study and the strategy used to stratify them will lead to more rational and efficient development of anticancer drugs.

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Carbonic anhydrase 2 (CAII) supports tumor blood endothelial cell survival under lactic acidosis in the tumor microenvironment

Annan, DA., Maishi, N., Soga T., Dawood, R. Li, C., Kikuchi, H., Hojo, T., Morimoto, M., Kitamura, T., Alam, MT., Minowa, K., Shinohara, N., Nam, JM., Hida, Y., Hida, K.

Cell Commun. Signal. 17 ( 1 ) 169 2019.12

Research paper (scientific journal), Joint Work, Accepted

Background: Tumor endothelial cells (TECs) perform tumor angiogenesis, which is essential for tumor growth and metastasis. Tumor cells produce large amounts of lactic acid from glycolysis; however, the mechanism underlying the survival of TECs to enable tumor angiogenesis under high lactic acid conditions in tumors remains poorly understood.
Methodology: The metabolomes of TECs and normal endothelial cells (NECs) were analyzed by capillary electrophoresis time-of-flight mass spectrometry. The expressions of pH regulators in TECs and NECs were determined by quantitative reverse transcription-PCR. Cell proliferation was measured by the MTS assay. Western blotting and ELISA were used to validate monocarboxylate transporter 1 and carbonic anhydrase 2 (CAII) protein expression within the cells, respectively. Human tumor xenograft models were used to access the effect of CA inhibition on tumor angiogenesis. Immunohistochemical staining was used to observe CAII expression, quantify tumor microvasculature, microvessel pericyte coverage, and hypoxia.
Results: The present study shows that, unlike NECs, TECs proliferate in lactic acidic. TECs showed an upregulated CAII expression both in vitro and in vivo. CAII knockdown decreased TEC survival under lactic acidosis and nutrient-replete conditions. Vascular endothelial growth factor A and vascular endothelial growth factor receptor signaling induced CAII expression in NECs. CAII inhibition with acetazolamide minimally reduced tumor angiogenesis in vivo. However, matured blood vessel number increased after acetazolamide treatment, similar to bevacizumab treatment. Additionally, acetazolamide-treated mice showed decreased lung metastasis.
Conclusion: These findings suggest that due to their effect on blood vessel maturity, pH regulators like CAII are promising targets of antiangiogenic therapy. Video Abstract.

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Mutant IDH1 confers resistance to energy stress in normal biliary cells through PFKP-induced aerobic glycolysis and AMPK activation

Fujiwara, H., Tateishi, K., Misumi, K., Hayashi, A., Igarashi, K, Kato, H., Nakatsuka, T., Suzuki, N., Yamamoto, K., Kudo, Y., Hayakawa, Y., Nakagawa, H., Tanaka, Y., Ijichi, H., Kogure, H, Nakai, Y, Isayama, H., Hasegawa, K., Fukayama, M., Soga, T., Koike, K..

Sci. Rep. 9 ( 1 ) 18859 2019.12

Research paper (scientific journal), Joint Work, Accepted

Metabolism is a critical regulator of cell fate determination. Recently, the significance of metabolic reprogramming in environmental adaptation during tumorigenesis has attracted much attention in cancer research. Recurrent mutations in the isocitrate dehydrogenase (IDH) 1 or 2 genes have been identified in several cancers, including intrahepatic cholangiocarcinoma (ICC). Mutant IDHs convert α-ketoglutarate (α-KG) to 2-hydroxyglutarate (2-HG), which affects the activity of multiple α-KG-dependent dioxygenases including histone lysine demethylases. Although mutant IDH can be detected even in the early stages of neoplasia, how IDH mutations function as oncogenic drivers remains unclear. In this study, we aimed to address the biological effects of IDH1 mutation using intrahepatic biliary organoids (IBOs). We demonstrated that mutant IDH1 increased the formation of IBOs as well as accelerated glucose metabolism. Gene expression analysis and ChIP results revealed the upregulation of platelet isoform of phosphofructokinase-1 (PFKP), which is a rate-limiting glycolytic enzyme, through the alteration of histone modification. Knockdown of the Pfkp gene alleviated the mutant IDH1-induced increase in IBO formation. Notably, the high expression of PFKP was observed more frequently in patients with IDH-mutant ICC compared to in those with wild-type IDH (p < 0.01, 80.9% vs. 42.5%, respectively). Furthermore, IBOs expressing mutant IDH1 survived the suppression of ATP production caused by growth factor depletion and matrix detachment by retaining high ATP levels through 5' adenosine monophosphate-activated protein kinase (AMPK) activation. Our findings provide a systematic understanding as to how mutant IDH induces tumorigenic preconditioning by metabolic rewiring in intrahepatic cholangiocytes.

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Metabolic adaptation to glycolysis is a basic defense mechanism of macrophages for Mycobacterium tuberculosis infection

Osada-Oka, M., Goda, N., Saiga, H., Yamamoto, M., Takeda, K., Ozeki, Y., Yamagchi, T., Soga, T., Tateishi, Y., Miura, K., Okuzaki, D., Kobayashi, K., *Matsumoto, S.

Int. Immunol. 31 ( 12 ) 781 - 793 2019.11

Research paper (scientific journal), Joint Work, Accepted

Macrophages are major components of tuberculosis (TB) granulomas and are responsible for host defenses against the intracellular pathogen, Mycobacterium tuberculosis. We herein showed the strong expression of hypoxia-inducible factor-1α (HIF-1α) in TB granulomas and more rapid death of HIF-1α-conditional knockout mice than wild-type (WT) mice after M. tuberculosis infection. Although interferon-γ (IFN-γ) is a critical host-protective cytokine against intracellular pathogens, HIF-1-deficient macrophages permitted M. tuberculosis growth even after activation with IFN-γ. These results prompted us to investigate the role of HIF-1α in host defenses against infection. We found that the expression of lactate dehydrogenase-A (LDH-A) was controlled by HIF-1α in M. tuberculosis-infected macrophages IFN-γ independently. LDH-A is an enzyme that converts pyruvate to lactate and we found that the intracellular level of pyruvate in HIF-1α-deficient bone marrow-derived macrophages (BMDMs) was significantly higher than in WT BMDMs. Intracellular bacillus replication was enhanced by an increase in intracellular pyruvate concentrations, which were decreased by LDH-A. Mycobacteria in phagosomes took up exogenous pyruvate more efficiently than glucose, and used it as the feasible carbon source for intracellular growth. These results demonstrate that HIF-1α prevents the hijacking of pyruvate in macrophages, making it a fundamental host-protective mechanism against M. tuberculosis.

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A metabolic profile of routine needle biopsies identified tumor type specific metabolic signatures for breast cancer stratification: a pilot study

Harada-Shoji, N., Soga, T., Tada, H., Miyashita, M., Harada, M., Watanabe, G., Hamanaka, Y., Sato, A., Suzuki, T., Suzuki, A., Ishida, T.

Metabolomics 15 ( 11 ) 147 2019.11

Research paper (scientific journal), Joint Work, Accepted, ISSN 15733882

Introduction: Metabolomics has recently emerged as a tool for understanding comprehensive tumor-associated metabolic dysregulation. However, only limited application of this technology has been introduced into the clinical setting of breast cancer.
Objectives: The aim of this study was to determine the feasibility of metabolome analysis using routine CNB/VAB samples from breast cancer patients and to elucidate metabolic signatures using metabolic profiling.
Methods: After breast cancer screenings, 20 consecutive patients underwent CNB/VAB, and diagnosed with benign, DCIS and IDC by histology. Metabolome analysis was performed using CE-MS. Differential metabolites were then analyzed and evaluated with MetaboAnalyst 4.0.
Results: We measured 116-targeted metabolites involved in energy metabolism. Principal component analysis and unsupervised hierarchical analysis revealed a distinct metabolic signature unique to namely "pure" IDC samples, whereas that of DCIS was similar to benign samples. Pathway analysis unveiled the most affected pathways of the "pure" IDC metabotype, including "pyrimidine," "alanine, aspartate, and glutamate" and "arginine and proline" pathways.
Conclusions: Our proof-of-concept study demonstrated that CE-MS-based CNB/VAB metabolome analysis is feasible for implementation in routine clinical settings. The most affected pathways in this study may contribute to improved breast cancer stratification and precision medicine.

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MITF controls the TCA cycle to modulate the melanoma hypoxia response

Louphrasitthiphol P., Ledaki I., Chauhan J., Falletta P., Siddaway R., Buffa FM., Mole DR., Soga T., Goding CR.

Pigment. Cell Melanoma. Res. 32 ( 6 ) 792 - 808 2019.11

Research paper (scientific journal), Joint Work, Accepted, ISSN 17551471

In response to the dynamic intra-tumor microenvironment, melanoma cells adopt distinct phenotypic states associated with differential expression of the microphthalmia-associated transcription factor (MITF). The response to hypoxia is driven by hypoxia-inducible transcription factors (HIFs) that reprogram metabolism and promote angiogenesis. HIF1α indirectly represses MITF that can activate HIF1α expression. Although HIF and MITF share a highly related DNA-binding specificity, it is unclear whether they co-regulate subset of target genes. Moreover, the genomewide impact of hypoxia on melanoma and whether melanoma cell lines representing different phenotypic states exhibit distinct hypoxic responses is unknown. Here we show that three different melanoma cell lines exhibit widely different hypoxia responses with only a core 23 genes regulated in common after 12 hr in hypoxia. Surprisingly, under hypoxia MITF is transiently up-regulated by HIF1α and co-regulates a subset of HIF targets including VEGFA. Significantly, we also show that MITF represses itself and also regulates SDHB to control the TCA cycle and suppress pseudo-hypoxia. Our results reveal a previously unsuspected role for MITF in metabolism and the network of factors underpinning the hypoxic response in melanoma.

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Association between dyslipidemia and plasma levels of branched-chain amino acids in the Japanese population without diabetes mellitus

Fukushima, K., Harada, S., Takeuchi, A., Kurihara, A., Iida, M., Fukai, K., Kuwabara, K., Kato, S., Matsumoto, M., Hirata, A., Akiyama, M., Tomita, M., Hirayama, A., Sato, A., Suzuki, C., Sugimoto, M., Soga, T., Sugiyama, D., Takebayashi, T.

J. Clini. Lipidol 13 ( 6 ) 932 - 939 2019.11

Research paper (scientific journal), Joint Work, Accepted, ISSN 19332874

Background: Branched-chain amino acids (BCAAs) play a key role in energy homeostasis.
Objective: We aimed to investigate the association between plasma BCAA levels and dyslipidemia in the Japanese population without diabetes mellitus.
Methods: This cross-sectional study included 4952 participants without diabetes mellitus, enrolled in the Tsuruoka Metabolomic Cohort Study. Plasma BCAA levels were measured by capillary electrophoresis-mass spectrometry. Correlations between lipid and BCAA profiles were evaluated by sex-stratified multiple linear regression analyses, after adjusting for confounders. Logistic regression was used to identify associations between BCAAs and metabolic dyslipidemia (MD) defined as triglyceride levels ≥150 mg/dL, high-density lipoprotein cholesterol levels ≤40 mg/dL for men and ≤50 mg/dL for women, or low-density lipoprotein cholesterol (LDL-C) levels ≥140 mg/dL.
Results: In both sexes, the levels of individual BCAAs and the total BCAA levels correlated positively with triglyceride levels and negatively with high-density lipoprotein cholesterol levels. Valine, leucine, and total BCAA levels were weakly and positively correlated with LDL-C levels. Increased BCAA levels showed positive associations with MD. However, associations between BCAAs and elevated LDL-C levels were unclear. Furthermore, the associations between BCAA levels and MD regardless of fasting blood sugar (FBS) levels (high or low). Although valine, leucine, and total BCAA levels were weakly associated with elevated LDL-C levels in the high-FBS group, no such association was observed in the low-FBS group.
Conclusions: BCAAs might be associated with MD independently of the FBS level and might play an important role in lipid metabolism and dyslipidemia.

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Metabolome Analysis Reveals Dermal Histamine Accumulation in Murine Dermatitis Provoked by Genetic Deletion of P-Glycoprotein and Breast Cancer Resistance Protein

Hashimoto, N., Nakamichi, N., Nanmo, H., Kimura, K., Masuo, Y., Sakai, Y., Schinkel, A.H., Sato, S., Soga, T., Kato, Y.

Pharm. Res. 36 ( 11 ) 158 2019.11

Research paper (scientific journal), Joint Work, Accepted, ISSN 07248741

Purpose: P-glycoprotein (P-gp) and breast cancer resistance protein (BCRP) are xenobiotic transporters which pump out variety types of compounds, but information on their interaction with endogenous substrates in the skin is limited. The purpose of the present study was to clarify possible association of these transporters in dermal accumulation of inflammatory mediators. Methods: Dermatitis model was constructed by repeated topical application of oxazolone in wild-type, and P-gp and BCRP gene triple knockout (Mdr1a/1b/Bcrp−/−) mice to observe difference in phenotype. Target metabolome analysis of 583 metabolites was performed using skin and plasma. Results: Dermatitis and scratching behavior in dermatitis model of Mdr1a/1b/Bcrp−/− mice were more severe than wild-type mice, suggesting protective roles of these transporters. This hypothesis was supported by the metabolome analysis which revealed that concentration of histamine and other dermatitis-associated metabolites like urate and serotonin in the dermatitis skin, but not normal skin, of Mdr1a/1b/Bcrp−/− mice was higher than that of wild-type mice. Gene expression of P-gp and BCRP was reduced in oxazolone-treated skin and the skin of patients with atopic dermatitis or psoriasis. Conclusions: These results suggest possible association of these efflux transporters with dermal inflammatory mediators, and such association could be observed in the dermatitis skin.

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Selective inhibition of mutant IDH1 by DS-1001b ameliorates aberrant histone modifications and impairs tumor activity in chondrosarcoma

Nakagawa M., Nakatani F., Matsunaga H., Seki T., Endo M., Ogawara Y., Machida Y., Katsumoto T., Yamagata K., Hattori A., Fujita S., Aikawa Y., Ishikawa T., Soga T., Kawai A., Chuman H., Yokoyama N., Fukushima S., Yahiro K., Kimura A., Shimada E., Hirose T., Fujiwara T., Setsu N., Matsumoto Y., Iwamoto Y., Nakashima Y., Kitabayashi I.

Oncogene 38 ( 42 ) 6835 - 6849 2019.10

Research paper (scientific journal), Joint Work, Accepted, ISSN 09509232

Chondrosarcoma is the second most common malignant bone tumor. It is characterized by low vascularity and an abundant extracellular matrix, which confer these tumors resistance to chemotherapy and radiotherapy. There are currently no effective treatment options for relapsed or dedifferentiated chondrosarcoma, and new targeted therapies need to be identified. Isocitrate dehydrogenase (IDH) mutations, which are detected in ~50% of chondrosarcoma patients, contribute to malignant transformation by catalyzing the production of 2-hydroxyglutarate (2-HG), a competitive inhibitor of α-ketoglutarate-dependent dioxygenases. Mutant IDH inhibitors are therefore potential novel anticancer drugs in IDH mutant tumors. Here, we examined the efficacy of the inhibition of mutant IDH1 as an antitumor approach in chondrosarcoma cells in vitro and in vivo, and investigated the association between the IDH mutation and chondrosarcoma cells. DS-1001b, a novel, orally bioavailable, selective mutant IDH1 inhibitor, impaired the proliferation of chondrosarcoma cells with IDH1 mutations in vitro and in vivo, and decreased 2-HG levels. RNA-seq analysis showed that inhibition of mutant IDH1 promoted chondrocyte differentiation in the conventional chondrosarcoma L835 cell line and caused cell cycle arrest in the dedifferentiated JJ012 cell line. Mutant IDH1-mediated modulation of SOX9 and CDKN1C expression regulated chondrosarcoma tumor progression, and DS-1001b upregulated the expression of these genes via a common mechanism involving the demethylation of H3K9me3. DS-1001b treatment reversed the epigenetic changes caused by aberrant histone modifications. The present data strongly suggest that inhibition of mutant IDH1 is a promising therapeutic approach in chondrosarcoma, particularly for the treatment of relapsed or dedifferentiated chondrosarcoma.

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Phosphoethanolamine Accumulation Protects Cancer Cells under Glutamine Starvation through Downregulation of PCYT2

Osawa T., Shimamura T., Saito K., Hasegawa Y., Ishii N., Nishida M., Ando R., Kondo A., Anwar M., Tsuchida R., Hino S., Sakamoto A., Igarashi K., Saitoh K., Kato K., Endo K., Yamano S., Kanki Y., Matsumura Y., Minami T., Tanaka T., Anai M., Wada Y., Wanibuchi H., Hayashi M., Hamada A., Yoshida M., Yachida S., Nakao M., Sakai J., Aburatani H., Shibuya M., Hanada K., Miyano S., Soga T., Kodama T.

Cell Rep. 29 ( 1 ) 89 - 103.e7 2019.10

Research paper (scientific journal), Joint Work, Accepted

Tolerance to severe tumor microenvironments, including hypoxia and nutrient starvation, is a common feature of aggressive cancer cells and can be targeted. However, metabolic alterations that support cancer cells upon nutrient starvation are not well understood. Here, by comprehensive metabolome analyses, we show that glutamine deprivation leads to phosphoethanolamine (PEtn) accumulation in cancer cells via the downregulation of PEtn cytidylyltransferase (PCYT2), a rate-limiting enzyme of phosphatidylethanolamine biosynthesis. PEtn accumulation correlated with tumor growth under nutrient starvation. PCYT2 suppression was partially mediated by downregulation of the transcription factor ELF3. Furthermore, PCYT2 overexpression reduced PEtn levels and tumor growth. In addition, PEtn accumulation and PCYT2 downregulation in human breast tumors correlated with poor prognosis. Thus, we show that glutamine deprivation leads to tumor progression by regulating PE biosynthesis via the ELF3-PCYT2 axis. Furthermore, manipulating glutamine-responsive genes could be a therapeutic approach to limit cancer progression.

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Fructose Increases the Activity of Sodium Hydrogen Exchanger in Renal Proximal Tubules that is Dependent on Ketohexokinase

Hayasaki, T., Ishimoto, T., Doke, T., Hirayama, A., Soga, T., Furuhashi, K., Kato, N., Kosugi, T., Tsuboi, N., Lanaspa, MA., Johnson, RJ., Maruyama, S., Kadomatsu, K.

J. Nutr. Biochem. 71 ( - ) 54 - 62 2019.09

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

High fructose intake has been known to induce metabolic syndrome in laboratory animals and humans. Although fructose intake enhances sodium reabsorption and elevates blood pressure, role of fructose metabolism in this process has not been studied. Here we show that by ketohexokinase - the primary enzyme of fructose - is involved in regulation of renal sodium reabsorption and blood pressure via activation of the sodium hydrogen exchanger in renal proximal tubular cells. First, wild-type and ketohexokinase knockout mice (Male, C57BL/6) were fed fructose water or tap water with or without a high salt diet. Only wild type mice fed the combination of fructose water and high salt diet displayed increased systolic blood pressure and decreased urinary sodium excretion. In contrast, ketohexokinase knockout mice were protected. Second, urinary sodium excretion after intraperitoneal saline administration was reduced with the decreased phosphorylation of sodium hydrogen exchanger 3 in fructose-fed WT; these changes were not observed in the ketohexokinase knockout mice, however. Third, knockdown of ketohexokinase attenuated fructose-mediated increases of NHE activity with decreased cAMP levels in porcine renal proximal tubular cells (LLC-PK1). In conclusion, fructose metabolism by ketohexokinase increases sodium hydrogen exchanger activity in renal proximal tubular cells via decreased intracellular cAMP level, resulting in increased renal sodium reabsorption and blood pressure in mice.
Keywords: Blood pressure; Fructose; Ketohexokinase; Kidney; NHE3; Sodium reabsorption.
Copyright © 2019 Elsevier Inc. All rights reserved.

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BCAA catabolism in brown fat controls energy homeostasis through SLC25A44

Yoneshiro T., Wang, Q., Tajima K., Matsushita M., Maki H., Igarashi K., Dai Z., White PJ., McGarrah RW., Ilkayeva OR., Deleye Y., Oguri Y., Kuroda M., Ikeda K., Li H., Ueno A., Ohishi M., Ishikawa T., Kim K., Chen Y., Sponton CH., Pradhan RN., Majd H., Greiner VJ., Yoneshiro M., Brown Z., Chondronikola M., Takahashi H., Goto T., Kawada T., Sidossis L., Szoka FC., McManus MT., Saito M., Soga T., Kajimura S.

Nature 572 ( 7771 ) 614 - 619 2019.08

Research paper (scientific journal), Joint Work, Accepted, ISSN 00280836

Branched-chain amino acid (BCAA; valine, leucine and isoleucine) supplementation is often beneficial to energy expenditure; however, increased circulating levels of BCAA are linked to obesity and diabetes. The mechanisms of this paradox remain unclear. Here we report that, on cold exposure, brown adipose tissue (BAT) actively utilizes BCAA in the mitochondria for thermogenesis and promotes systemic BCAA clearance in mice and humans. In turn, a BAT-specific defect in BCAA catabolism attenuates systemic BCAA clearance, BAT fuel oxidation and thermogenesis, leading to diet-induced obesity and glucose intolerance. Mechanistically, active BCAA catabolism in BAT is mediated by SLC25A44, which transports BCAAs into mitochondria. Our results suggest that BAT serves as a key metabolic filter that controls BCAA clearance via SLC25A44, thereby contributing to the improvement of metabolic health.

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Metabolomic profiling reveals salivary hypotaurine as a potential early detection marker for medication-related osteonecrosis of the jaw

Yatsuoka, W., Ueno, T., Miyano, K., Uezono, Y., Enomoto, A., Kaneko, M., Ota, S., Soga, T., Sugimoto, M., Ushijima, T.

PLoS ONE 14 ( 8 ) e0220712 2019.08

Research paper (scientific journal), Joint Work, Accepted

Medication-related osteonecrosis of the jaw (MRONJ) is a rare but serious adverse event of bone-modifying agents used to prevent bone complications in cancer patients with bone metastasis. Currently, early treatment is the only way to prevent further progression, as the pathogenesis of MRONJ has not yet been elucidated, and a standard treatment has not been established. The aim of this study was to identify a marker for early detection marker of MRONJ by exploring substances in saliva specific to MRONJ at an early stage. We collected salivary samples from 17 patients with MRONJ and conducted metabolomic analyses using capillary electrophoresis mass spectrometry for non-targeted analysis of hydrophilic metabolites. In the screening cohort, we compared the saliva of patients with stage ≥1 advanced MRONJ (n = 9) with that of controls without MRONJ before chemotherapy (n = 9). The top 5 most elevated salivary metabolites were histamine, 3-(4-hydroxyphenyl)propionate, malonate, carnosine, and hypotaurine. In the validation cohort, we analyzed additional patients with stage ≥1 advanced MRONJ (n = 8) and controls without MRONJ after chemotherapy (n = 9), confirming a significant 2.28-fold elevation in the salivary concentration of hypotaurine. These results revealed elevated salivary hypotaurine concentration as a potential marker for the early detection of MRONJ.

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IMP dehydrogenase-2 drives aberrant nucleolar activity and promotes tumorigenesis in glioblastoma

Kofuji, S., Hirayama, A., Eberhardt, A.O., Kawaguchi R., Sugiura, Y., Sampetrean, O., Ikeda, Y., Warren, M., Sakamoto, N., Kitahara, S., Yohino, H., Yamashita, D., Sumita, K., Wofe, K., Lange, L., Ikeda, S., Shimada, H., Minami, N., Malhotra, A., Morioka, S., Ban, Y., Asano, M., Flanary, V.L., Ramkissoon, A., Chow, L.M.L., Kiyokawa, J., Mahimo, T., Lucey, G., Mareninov, S., Ozawa, T., Onishi, N., Okumura, K., Terakawa, J., Daikoku, T., Wise-Draper, T., Majd, N., Kofuji, K., Sasaki, M., Mori, M., Kanemura, Y., Smith, E.P., Anastasiou, D., Wakimoto, H., Holland, E.C., Yong, W.H., Horbinski, C., Nakano, I., Deberardinis, R.J., Bachoo, R., Mischel, P.S., Yasui, W., Suematsu, M., Saya, H., Soga, T., Grummt, I., Bierhoff, H., Sasaki, AT.

Nat. Cell Biol. 21 ( 8 ) 1003 - 1014 2019.08

Research paper (scientific journal), Joint Work, Accepted, ISSN 14657392

In many cancers, high proliferation rates correlate with elevation of rRNA and tRNA levels, and nucleolar hypertrophy. However, the underlying mechanisms linking increased nucleolar transcription and tumorigenesis are only minimally understood. Here we show that IMP dehydrogenase-2 (IMPDH2), the rate-limiting enzyme for de novo guanine nucleotide biosynthesis, is overexpressed in the highly lethal brain cancer glioblastoma. This leads to increased rRNA and tRNA synthesis, stabilization of the nucleolar GTP-binding protein nucleostemin, and enlarged, malformed nucleoli. Pharmacological or genetic inactivation of IMPDH2 in glioblastoma reverses these effects and inhibits cell proliferation, whereas untransformed glia cells are unaffected by similar IMPDH2 perturbations. Impairment of IMPDH2 activity triggers nucleolar stress and growth arrest of glioblastoma cells even in the absence of functional p53. Our results reveal that upregulation of IMPDH2 is a prerequisite for the occurance of aberrant nucleolar function and increased anabolic processes in glioblastoma, which constitutes a primary event in gliomagenesis.

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Adaptation to HIF1α deletion in hypoxic cancer cells by upregulation of GLUT14 and creatine metabolism

Valli, A., Morotti, M., Zois, CE., Albers, PK., Soga, T, Feldinger, K., Fischer, R., Frejno, M., McIntyre, A., Bridges, E., Haider, S., Buffa, FM., Baban, D., Rodriguezm, M., Yanes, O., Whittington, HJ., Lake, HA., Zervou, S., Lygate, CA., Kessler, BM., Harris, AL.

Mol. Cancer Res 17 ( 7 ) 1531 - 1544 2019.07

Research paper (scientific journal), Joint Work, Accepted, ISSN 15417786

Hypoxia-inducible factor 1α is a key regulator of the hypoxia response in normal and cancer tissues. It is well recognized to regulate glycolysis and is a target for therapy. However, how tumor cells adapt to grow in the absence of HIF1α is poorly understood and an important concept to understand for developing targeted therapies is the flexibility of the metabolic response to hypoxia via alternative pathways. We analyzed pathways that allow cells to survive hypoxic stress in the absence of HIF1α, using the HCT116 colon cancer cell line with deleted HIF1α versus control. Spheroids were used to provide a 3D model of metabolic gradients. We conducted a metabolomic, transcriptomic, and proteomic analysis and integrated the results. These showed surprisingly that in three-dimensional growth, a key regulatory step of glycolysis is Aldolase A rather than phosphofructokinase. Furthermore, glucose uptake could be maintained in hypoxia through upregulation of GLUT14, not previously recognized in this role. Finally, there was a marked adaptation and change of phosphocreatine energy pathways, which made the cells susceptible to inhibition of creatine metabolism in hypoxic conditions. Overall, our studies show a complex adaptation to hypoxia that can bypass HIF1α, but it is targetable and it provides new insight into the key metabolic pathways involved in cancer growth. IMPLICATIONS: Under hypoxia and HIF1 blockade, cancer cells adapt their energy metabolism via upregulation of the GLUT14 glucose transporter and creatine metabolism providing new avenues for drug targeting.
©2019 American Association for Cancer Research.

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Metagenomic and metabolimic analyses reveal distinct stage-specific phenotypes of the gut microbiota in colorectal cancer

Yachida, S., Mizutani, S., Shiroma, H., Shiba, S., Nakajima, T., Sakamoto, T., Watanabe, H., Masuda, K., Nishimoto, Y., Kubo, M., Hosoda, F., Rokutan, H., Matsumoto, M., Takamaru, H., Yamada, M., Matsuda, T., Iwasaki, M., Yamaji, T., Yachida, T., Soga, T., Kurokawa, K., Toyoda, A., Ogura, Y., Hayashi, T., Hatakeyama, M., Nakagama, H., Saito, Y., Fukuda, S., Shibata, T., Yamada, T.

Nat. Med. 25 ( 6 ) 968 - 976 2019.06

Research paper (scientific journal), Joint Work, Accepted

In most cases of sporadic colorectal cancers, tumorigenesis is a multistep process, involving genomic alterations in parallel with morphologic changes. In addition, accumulating evidence suggests that the human gut microbiome is linked to the development of colorectal cancer. Here we performed fecal metagenomic and metabolomic studies on samples from a large cohort of 616 participants who underwent colonoscopy to assess taxonomic and functional characteristics of gut microbiota and metabolites. Microbiome and metabolome shifts were apparent in cases of multiple polypoid adenomas and intramucosal carcinomas, in addition to more advanced lesions. We found two distinct patterns of microbiome elevations. First, the relative abundance of Fusobacterium nucleatum spp. was significantly (P < 0.005) elevated continuously from intramucosal carcinoma to more advanced stages. Second, Atopobium parvulum and Actinomyces odontolyticus, which co-occurred in intramucosal carcinomas, were significantly (P < 0.005) increased only in multiple polypoid adenomas and/or intramucosal carcinomas. Metabolome analyses showed that branched-chain amino acids and phenylalanine were significantly (P < 0.005) increased in intramucosal carcinomas and bile acids, including deoxycholate, were significantly (P < 0.005) elevated in multiple polypoid adenomas and/or intramucosal carcinomas. We identified metagenomic and metabolomic markers to discriminate cases of intramucosal carcinoma from the healthy controls. Our large-cohort multi-omics data indicate that shifts in the microbiome and metabolome occur from the very early stages of the development of colorectal cancer, which is of possible etiological and diagnostic importance.

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Metabolome profiling of various seaweed species discriminates between brown, red, and green algae

Hamid, SS., Wakayama M., Ichihara K., Sakurai K., Ashino Y., Kadowaki R., Soga T., Tomita M.

Planta 249 ( 6 ) 1921 - 1947 2019.06

Research paper (scientific journal), Joint Work, Accepted, ISSN 00320935

Among seaweed groups, brown algae had characteristically high concentrations of mannitol, and green algae were characterised by fructose. In red algae, metabolite profiles of individual species should be evaluated. Seaweeds are metabolically different from terrestrial plants. However, general metabolite profiles of the three major seaweed groups, the brown, red, and green algae, and the effect of various extraction methods on metabolite profiling results have not been comprehensively explored. In this study, we evaluated the water-soluble metabolites in four brown, five red, and two green algae species collected from two sites in northern Japan, located in the Sea of Japan and the Pacific Ocean. Freeze-dried seaweed samples were processed by methanol-water extraction with or without chloroform and analysed by capillary electrophoresis- and liquid chromatography-mass spectrometry for metabolite characterisation. The metabolite concentration profiles showed distinctive characteristic depends on species and taxonomic groups, whereas the extraction methods did not have a significant effect. Taxonomic differences between the various seaweed metabolite profiles were well defined using only sugar metabolites but no other major compound types. Mannitol was the main sugar metabolites in brown algae, whereas fructose, sucrose, and glucose were found at high concentrations in green algae. In red algae, individual species had some characteristic metabolites, such as sorbitol in Pyropia pseudolinearis and panose in Dasya sessilis. The metabolite profiles generated in this study will be a resource and provide guidance for nutraceutical research studies because the information about metabolites in seaweeds is still very limited compared to that of terrestrial plants.

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Synthetic miR-143 Exhibited an Anti-Cancer Effect via the Downregulation of K-RAS Networks of Renal Cell Cancer Cells In Vitro and In Vivo

Takai, T., Tsujino, T., Yoshikawa, Y., Inamoto, T., Sugito, N., Kuranaga, Y., Heishima, K., Soga, T., Hayashi, K., Miyata, K., Kataoka, K., Azuma, H., Akao, Y.

Mol. Ther. 27 ( 5 ) 1017 - 1027 2019.05

Research paper (scientific journal), Joint Work, Accepted, ISSN 15250016

To understand the role of RAS-signaling networks in the pathogenesis of renal cell carcisnoma, we clarified the relationship between miR-143 and RAS. The expression of miR-143 was extremely downregulated in tumor tissues from renal cell carcinoma patients compared with that in the adjacent normal tissues and Caki-1 cells. We developed a synthetic miR-143#12, and we found that the ectopic expression of it inhibited cell growth with autophagy in Caki-1 cells. Also, the expression level of c-Myc was markedly decreased, resulting in the perturbation of cancer-specific energy metabolism by negatively modulating the expression of GLUT1 and the PTBP1/PKMs axis. A partial metabolic shift from glycolysis to oxidative phosphorylation induced autophagy through increasing the intracellular level of reactive oxygen species (ROS). In an in vivo study, the potent anti-tumor activity of polyion complex (PIC)-loaded miR-143#12 (miR-143#12/PIC) was shown by systemic administration of it to Caki-1 cell-xenografted mice. Higher levels of miR-143 were found in both blood and tumor tissues after the systemic administration with miR-143#12/PIC compared to those with lipoplexes in the xenografted mice. These findings indicated that this synthetic miR-143#12 induced a marked growth inhibition by impairing K-RAS-signaling networks in vitro and in vivo.
Copyright © 2019 The Author(s). Published by Elsevier Inc. All rights reserved.

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Gut microbiome-derived phenyl sulfate contributes to albuminuria in diabetic kidney disease

Kikuchi K., Saigusa D., Kanemitsu Y., Matsumoto Y., Thanai P., Suzuki N., Mise K., Yamaguchi H., Nakamura T., Asaji K., Mukawa C., Tsukamoto H., Sato T., Oikawa Y., Iwasaki T., Oe Y., Tsukimi T., Fukuda N., Ho H., Nanto-Hara F., Ogura J., Saito R., Nagao S., Ohsaki Y., Shimada S., Suzuki T., Toyohara T., Mishima E., Shima H., Akiyama Y., Akiyama Y., Ichijo M., Matsuhashi T., Matsuo A., Ogata Y., Yang C., Suzuki C., Breeggemann M., Heymann J., Shimizu M., Ogawa S., Takahashi N., Suzuki T., Owada Y., Kure S., Mano N., Soga T., Wada T., Kopp J., Fukuda S., Hozawa A., Yamamoto M., Ito S., Wada J., Tomioka Y., Abe T.

Nat. Commun. 10 ( 1 ) 1835 - - 2019.04

Research paper (scientific journal), Joint Work, Accepted

Diabetic kidney disease is a major cause of renal failure that urgently necessitates a breakthrough in disease management. Here we show using untargeted metabolomics that levels of phenyl sulfate, a gut microbiota-derived metabolite, increase with the progression of diabetes in rats overexpressing human uremic toxin transporter SLCO4C1 in the kidney, and are decreased in rats with limited proteinuria. In experimental models of diabetes, phenyl sulfate administration induces albuminuria and podocyte damage. In a diabetic patient cohort, phenyl sulfate levels significantly correlate with basal and predicted 2-year progression of albuminuria in patients with microalbuminuria. Inhibition of tyrosine phenol-lyase, a bacterial enzyme responsible for the synthesis of phenol from dietary tyrosine before it is metabolized into phenyl sulfate in the liver, reduces albuminuria in diabetic mice. Together, our results suggest that phenyl sulfate contributes to albuminuria and could be used as a disease marker and future therapeutic target in diabetic kidney disease.

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Autophagy regulates lipid metabolism through selective turnover of NCoR1

Saito, T., Kuma, A., Sugiura, Y., Ichimura, Y., Obata, M., Kitamura, H., Okuda, S., Lee, HC., Ikeda, K., Kanegae, Y., Saito, I., Auwerx, J., Motohashi, H., Suematsu, M., Soga, T., Yokomizo, T., Waguri, S., Mizushima, N., Komatsu M.

Nat. Commun. 10 ( 1 ) 1567 - - 2019.04

Research paper (scientific journal), Joint Work, Accepted

Selective autophagy ensures the removal of specific soluble proteins, protein aggregates, damaged mitochondria, and invasive bacteria from cells. Defective autophagy has been directly linked to metabolic disorders. However how selective autophagy regulates metabolism remains largely uncharacterized. Here we show that a deficiency in selective autophagy is associated with suppression of lipid oxidation. Hepatic loss of Atg7 or Atg5 significantly impairs the production of ketone bodies upon fasting, due to decreased expression of enzymes involved in β-oxidation following suppression of transactivation by PPARα. Mechanistically, nuclear receptor co-repressor 1 (NCoR1), which interacts with PPARα to suppress its transactivation, binds to the autophagosomal GABARAP family proteins and is degraded by autophagy. Consequently, loss of autophagy causes accumulation of NCoR1, suppressing PPARα activity and resulting in impaired lipid oxidation. These results suggest that autophagy contributes to PPARα activation upon fasting by promoting degradation of NCoR1 and thus regulates β-oxidation and ketone bodies production.

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