( 2 ) Nuclear receptors in health, age-related diseases and cancer
( 3 ) Mitochondrial respiratory super-complex and aging
( 4 ) Cancer genomics and epigenomics
2.Vitamin K and age-related diseases
( 1 ) Vitamin K and locomotive syndrome
( 2 ) Roles of γ-glutamyl carboxylase and SXR in health and diseases
The research group of Systems Aging Science and Medicine is working mainly on biological aging and age-related diseases mediated by nuclear receptors with comprehensive multi-omics approach based on systems biology. Nuclear receptors are ligand-dependent transcription factors and comprise nuclear receptor superfamily based on the similarity of their domain structure. The nuclear receptors we are focusing on are estrogen receptor (ER), androgen receptor (AR) and steroid and xenobiotic receptor (SXR). We previously demonstrated that vitamin K is one of the ligands of SXR (Fig 1). Estrogen, androgen and vitamin K are shown or expected to have protective roles for various age-related diseases (Fig2). On the other hand, estrogen and androgen are accelerating factors for sex hormone-dependent cancers such as breast cancer and prostate cancer. We are studying genomic (Fig 3), epigenomic (Fig 4), and non-genomic (Fig 5) events caused by these nuclear receptors in the pathogenesis of age-related musculoskeletal diseases comprising locomotive syndrome (osteoporosis, osteoarthritis and sarcopenia), and hormone-dependent cancers. We are employing several innovative approaches such as genome-wide analyses using next-generation sequencers combined with genetically engineered animals, proteomics/metabolomics analyses, and real-time imaging of mitochondrial respiratory super-complex with high-resolution stimulated emission depletion (STED) microscopy (Fig 2). Our interests are to find new molecular mechanisms concerning the pathogenesis of these diseases and discover novel targets for their diagnosis, prevention and/or treatment. The ultimate aim is to extend life expectancy by overcoming hormone-dependent cancers, to extend ‘healthy life expectancy’ by preventing locomotive syndrome, and to contribute to human ‘Longevity and Health’ by clinical application of our discoveries.
1. Takayama K, Suzuki T, Fujimura T, Takahashi S, Inoue S: COBLL1 modulates cell morphology and facilitates androgen receptor genomic binding in advanced prostate cancer. Proc Natl Acad Sci U S A (in press)
2. Takayama K, Suzuki T, Tanaka T, Fujimura T, Takahashi S, Urano T, Ikeda K, Inoue S: TRIM25 enhances cell growth and cell survival by modulating p53 signals via interaction with G3BP2 in prostate cancer. Oncogene (in press)
3. Takayama K, Suzuki T, Fujimura T, Takahashi S, Inoue S: Association of USP10 with G3BP2 Inhibits p53 Signaling and Contributes to Poor Outcome in Prostate Cancer. Mol Cancer Res (in press)
4. Mitobe Y, Takayama K, Horie-Inoue K, Inoue S: Prostate cancer-associated lncRNAs. Cancer Lett 418, 159-166, 2018
5. Takayama K, Suzuki T, Fujimura T, Yamada Y, Takahashi S, Homma Y, Suzuki Y, Inoue S: Dysregulation of spliceosome gene expression in advanced prostate cancer by RNA-binding protein PSF. Proc Natl Acad Sci U S A, 114(39), 10461-10466, 2017
7. Kawabata H, Azuma K, Ikeda K, Sugitani I,Kinowaki K, Fujii T, Osaki A, Saeki T, Horie-Inoue K, Inoue S: TRIM44 Is a Poor Prognostic Factor for Breast Cancer Patients as a Modulator of NF-κB Signaling. Int. J. Mol. Sci 18(9). pii: E1931, 2017
8. Huang L, Zhang H, Cheng CY, Wen F, Tam POS, Zhao P, Chen H, Li Z, Chen L, Tai Z, Yamashiro K, Deng S, Zhu X, Chen W, Li C, Lu F, Li Y, Cheung CMG, Shi Y, Miyake M, Lin Y, Gong B, Liu X, Sim KS, Yang J, Mori K, Zhang X, Cackett PD, Tsujikawa M, Nishida K, Hao F, Ma S, Lin H, Chen J, Fei P, Lai TYY, Tang S, Laude A, Inoue S, Yeo IY, Sakurada Y, Zhou Y, Iijima H, Honda S, Lei C, Zhang L, Zheng H, Jiang D, Zhu X, Wong TY, Khor CC, Pang CP, Yoshimura N, Yang Z: A missense variant in FGD6 confers increased risk of polypoidal choroidal vasculopathy. Nat Genet 48, 640-647, 2016
9. Aihara H, Nakagawa T, Mizusaki H, Yoneda M, Kato M, Doiguchi M, Imamura Y, Higashi M, Ikura T, Hayashi T, Kodama Y, Oki M, Nakayama T, Edwin Cheung, Aburatani H, Takayama K, Koseki H, Inoue S, Takeshima Y, Ito T: Histone H2A T120 Phosphorylation Promotes Oncogenic Transformation via Upregulation of Cyclin D1. Mol Cell 64(1), 176-188, 2016
10.Misawa A, Takayama K, Urano T, Inoue S: Androgen-induced Long Noncoding RNA (lncRNA) SOCS2-AS1 Promotes Cell Growth and Inhibits Apoptosis in Prostate Cancer Cells. J Biol Chem 291(34), 17861-80, 2016
11.Obinata D, Takayama K, Fujiwara K, Suzuki T, Tsutsumi S, Fukuda N, Nagase H, Fujimura T, Urano T, Homma Y, Aburatani H, Takahashi S, Inoue S: Targeting Oct1 genomic function inhibits androgen receptor signaling and castration-resistant prostate cancer growth. Oncogene 35(49):6350-6358, 2016
12.Takayama K, Misawa A, Suzuki T, Takagi K, Hayashizaki Y, Fujimura T, Homma Y, Takahashi S, Urano T, Inoue S: TET2 repression by androgen hormone regulates global hydroxymethylation status and prostate cancer progression. Nat Commun 6, 8219, 2015.
13.Azuma K, Shiba S, Hasegawa T, Ikeda K, Urano T, Horie-Inoue K, Ouchi Y, Amizuka N, Inoue S: Osteoblast-specific γ-glutamyl carboxylase-deficient mice display enhanced bone formation with aberrant mineralization. J Bone Miner Res 30, 1245-1254, 2015.
14.Urano T, Shiraki M, Sasaki N, Ouchi Y, Inoue S: SLC25A24 as a novel susceptibility gene for low fat mass in humans and mice. J Clin Endocrinol Metab 100, E655-E663, 2015.
15.Takayama K, Suzuki T, Tsutsumi S, Fujimura T, Takahashi S, Homma Y, Urano T, Aburatani H, Inoue S: Integrative analysis of FOXP1 function reveals a tumor suppressive effect in prostate cancer. Mol Endocrinol 28, 2012-2024, 2014.
16.Takayama K, Suzuki T, Fujimura T, Urano T, Takahashi S, Homma Y, Inoue S: CtBP2 modulates the androgen receptor to promote prostate cancer progression. Cancer Res 74, 6542-6553, 2014.
17.Urano T, Shiraki M, Sasaki N, Ouchi Y, Inoue S: Large-scale analysis reveals a functional single-nucleotide polymorphism in the 5'-flanking region of PRDM16 gene associated with lean body mass. Aging Cell 13, 739-743, 2014.
18.Takayama K, Horie-Inoue K, Katayama S, Suzuki T, Tsutsumi S, Ikeda K, Urano T, Fujimura T, Takagi K, Takahashi S, Homma Y, Ouchi Y, Aburatani H, Hayashizaki Y, Inoue S: Androgen-responsive long noncoding RNA CTBP1-AS promotes prostate cancer. EMBO J 32, 1665-1680, 2013 and highlighted in "Have you seen?" pp.1653-1654.
19.Ikeda K, Shiba S, Horie-Inoue K, Shimokata K, Inoue S: A stabilizing factor for mitochondrial respiratory supercomplex assembly regulates energy metabolism in muscle. Nat Commun 4, 2147, 2013.
20.Takayama K, Horie-Inoue K, Suzuki T, Urano T, Ikeda K, Fujimura T, Takahashi S, Homma Y, Ouchi Y, Inoue S: TACC2 is an androgen-responsive cell cycle regulator promoting androgen-mediated and castration-resistant growth of prostate cancer. Mol Endocrinol 26, 748-761, 2012 and highlighted in "Editorial" p.715.
21.Murata T, Takayama K, Urano T, Fujimura T, Ashikari D, Obinata D, Horie-Inoue K, Takahashi S, Ouchi Y, Homma Y, Inoue S: 14-3-3ζ, a novel androgen-responsive gene, is upregulated in prostate cancer and promotes prostate cancer cell proliferation and survival. Clin Cancer Res 18, 5617-5627, 2012.
22.Urano T, Shiraki M, Ouchi Y, Inoue S: Association of circulating sclerostin levels with fat mass and metabolic disease-related markers in Japanese postmenopausal women. J Clin Endocrinol Metab 97, E1473-E1477, 2012.
23.Urano T, Shiraki M, Yagi H, Ito M, Sasaki N, Sato M, Ouchi Y, Inoue S: GPR98/Gpr98 gene is involved in the regulation of human and mouse bone mineral density. J Clin Endocrinol Metab 97, E565-E574, 2012.
24.Takayama K, Tsutsumi S, Katayama S, Okayama T, Horie-Inoue K, Ikeda K, Urano T, Kawazu C, Hasegawa A, Ikeo K, Gojyobori T, Ouchi Y, Hayashizaki Y, Aburatani H, Inoue S: Integration of cap analysis of gene expression and chromatin immunoprecipitation analysis on array reveals genome-wide androgen receptor signaling in prostate cancer cells. Oncogene 30, 619-630, 2011.
25.Takayama K, Tsutsumi S, Suzuki T, Horie-Inoue K, Ikeda K, Kaneshiro K, Fujimura T, Kumagai J, Urano T, Sakaki Y, Shirahige K, Sasano H, Takahashi S, Kitamura T, Ouchi Y, Aburatani H, Inoue S: Amyloid precursor protein is a primary androgen target gene that promotes prostate cancer growth. Cancer Res 69, 137-142, 2009.
26.Azuma K, Urano T, Horie-Inoue K, Hayashi S, Sakai R, Ouchi Y, Inoue S: Association of estrogen receptor and histone deacetylase 6 causes rapid deacetylation of tubulin in breast cancer cell. Cancer Res 69, 2935-2940, 2009.
27.Gack MU, Shin YC, Joo CH, Urano T, Liang C, Sun L, Takeuchi O, Akira S, Chen Z, Inoue S, Jung JU: TRIM25 RING-finger E3 ubiquitin ligase is essential for RIG-I-mediated antiviral activity. Nature 446, 916-921, 2007.
28.Ichikawa T, Horie-Inoue K, Ikeda K, Blumberg B, Inoue S: Steroid and xenobiotic receptor SXR mediates vitamin K2-activated transcription of extracellular matrix-related genes and collagen accumulation in osteoblastic cells. J Biol Chem 281, 16927-16934, 2006, Cover, and highlighted in “Paper of this week”.
29.Ogushi T, Takahashi S, Takeuchi T, Urano T, Horie-Inoue K, Kumagai J, Kitamura T, Ouchi Y, Muramatsu M, Inoue S: Estrogen receptor-binding fragment-associated antigen 9 is a tumor-promoting and prognostic factor for renal cell carcinoma. Cancer Res 65, 3700-3706, 2005.
30.Urano T, Saito T, Tsukui T, Fujita M, Hosoi T, Muramatsu M, Ouchi Y, Inoue S: Efp targets 14-3-3σ for proteolysis and promotes breast tumour growth. Nature 417, 871-875, 2002.