( 2 ) Nuclear receptors in health, age-related diseases and cancer
( 3 ) Mitochondrial respiratory supercomplex in health 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 disease
Profile
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 (Fig. 2). 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-related cancers. We are also studying the mechanisms of therapy resistance in hormone-related cancers (Fig. 6). We are employing several innovative approaches such as genome-wide analyses using next-generation sequencers combined with genetically engineered animals, patient-derived models, proteomics/metabolomics analyses, in vitro chemical array screening, and real-time imaging of mitochondrial respiratory super-complex with high-resolution stimulated emission depletion (STED) microscopy. Our interests are to find new molecular mechanisms concerning the pathogenesis of aging, as well as 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.
References
1. Azuma K, Osuka Y, Kojima N, Sasai H, Kim H, Inoue S: Association of vitamin K insufficiency with cognitive dysfunction in community-dwelling older adults. Front Nutri 8, 811831, 2022.
2. Sato K, Takayama K, Hashimoto M, Inoue S: Transcriptional and post-transcriptional regulations of amyloid-β precursor protein, APP. Front Aging 2, 721579, 2021.
3. Azuma K, Ikeda K, Suzuki T, Aogi K, Horie-Inoue K, Inoue S: TRIM47 activates NF-κB signaling via PKCε/PKD3 stabilization and contributes to endocrine therapy resistance in breast cancer. Proc Natl Acad Sci U S A 118, e2100784118, 2021.
4. Takayama K, Kosaka T, Suzuki T, Hongo H, Oya M, Fujimura T, Suzuki Y, Inoue S: Subtype-specific collaborative transcription factor networks are promoted by OCT4 in the progression of prostate cancer. Nat Commun 12, 3766, 2021.
5. Takayama K, Honma T, Suzuki T, Kondoh Y, Osada H, Suzuki Y, Yoshida M, Inoue S: Targeting epigenetic and post-transcriptional gene regulation by PSF impairs hormone therapy-refractory cancer growth. Cancer Res 81, 3495-3508, 2021.
6. Kamada S, Namekawa T, Ikeda K, Suzuki T, Kagawa M, Takeshita H, Yano A, Okamoto K, Ichikawa T, Horie-Inoue K, Kawakami S, Inoue S: Functional inhibition of cancer stemness-related protein DPP4 rescues tyrosine kinase inhibitor resistance in renal cell carcinoma. Oncogene 40, 3899-3913, 2021.
7. Takeiwa T, Ikeda K, Horie-Inoue K, Inoue S: Mechanisms of apoptosis-related long non-coding RNAs in ovarian cancer. Front Cell Dev Biol 9, 641963, 2021.
8. Hashimoto M, Ho G, Sugama S, Takenouchi T, Waragai M, Inoue S, Masliah E: Possible role of activin in the adiponectin paradox-induced progress of Alzheimer’s disease. J Alzheimers Dis 81, 451-458, 2021.
9. Shiba S, Ikeda K, Horie-Inoue K, Azuma K, Hasegawa T, Amizuka N, Tanaka T, Takeiwa T, Shibata Y, Koji T, Inoue S: Vitamin K-dependent γ-glutamyl carboxylase in Sertoli cells is essential for male fertility in mice. Mol Cell Biol MCB.00404-20, 2021 and Highlighted in “Spotlights” and Cover.
10.Takayama K, Fujimura T, Suzuki Y, Inoue S: Identification of long non-coding RNAs in advanced prostate cancer associated with androgen receptor splicing factors. Commun Biol 3, 393, 2020.
11.Namekawa T, Kitayama S, Ikeda K, Horie-Inoue K, Suzuki T, Okamoto K, Ichikawa T, Yano A, Kawakami S, Inoue S: HIF1α inhibitor 2-methoxyestradiol decreases NRN1 expression and represses in vivo and in vitro growth of patient-derived testicular germ cell tumor spheroids. Cancer Lett 489, 79-86, 2020.
12.Mitobe Y, Iino K, Takayama KI, Ikeda K, Suzuki T, Aogi K, Kawabata H, Suzuki Y, Horie-Inoue K, Inoue S: PSF promotes ER-positive breast cancer progression via posttranscriptional regulation of ESR1 and SCFD2. Cancer Res 80, 2230-2242, 2020.
13.Mitobe Y, Ikeda K, Suzuki T, Takagi K, Kawabata H, Horie-Inoue K, Inoue S: ESR1-stabilizing lncRNA TMPO-AS1 promotes hormone-refractory breast cancer progression. Mol Cell Biol 39, e00261-19, 2019. and Highlighted in "Spotlight" and Cover.
14.Ikeda K, Horie-Inoue K, Suzuki T, Hobo R, Nakasato N, Takeda S, Inoue S: Mitochondrial supercomplex assembly promotes breast and endometrial tumorigenesis by metabolic alterations and enhanced hypoxia tolerance. Nat Commun 10, 4108, 2019.
15.Shiba S, Ikeda K, Suzuki T, Shintani D, Okamoto K, Horie-Inoue K, Hasegawa K, Inoue S: Hormonal regulation of patient-derived endometrial cancer stem-like cells generated by three-dimensional culture. Endocrinology 160, 1895-1906, 2019 and Highlighted in "eNews", pii: en.2019-00362.
16.Namekawa T, Ikeda K, Horie-Inoue K, Suzuki T, Okamoto K, Ichikawa T, Yano, A, Kawakami S, Inoue S: ALDH1A1 in patient-derived bladder cancer spheroids activates retinoic acid signaling leading to TUBB3 overexpression and tumor progression. Int J Cancer 146, 1099-1113, 2019.
17.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 115, 4975-4980, 2018.
18.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 37, 2165-2180, 2018.
19.Miyazaki T, Ikeda K, Sato W, Horie-Inoue K, Inoue S: Extracellular vesicle-mediated EBAG9 transfer from cancer cells to tumor microenvironment promotes immune escape and tumor progression. Oncogenesis 7, 7, 2018
20.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, 10461-10466, 2017.
22.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, 17861-80, 2016.
23.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, 6350-6358, 2016.
24.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.
25.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.
26.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.
27.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.
28.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.
29.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.
30.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.
31.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.
32.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.
33.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.
34.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.
35.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.
36.Azuma K, Urano T, Horie-Inoue K, Hayashi S, Sakai R, Ouchi Y, Inoue S: Association of estrogen receptor α and histone deacetylase 6 causes rapid deacetylation of tubulin in breast cancer cell. Cancer Res 69, 2935-2940, 2009.
37.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.
38.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".
39.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.
40.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.
