SECTION

Division of Gene Structure and Function Division of Gene Regulation and Signal Transduction
Division of Developmental Biology Division of Pathophysiology
Division of Gene Therapy and Genome Editing  
Division  of Gene Regulation and Signal Transduction
概要
Research Summary
 

 Our research aim is to understand the molecular mechanisms and gene regulatory network primarily controlled by sex steroid hormones. We focus on the study of estrogen and androgen, which initially play essential roles in the development and maintenance of female and male reproductive organs, respectively. Hormone decline or deficiency causes functional changes of various organs including metabolic and immune systems. Sex hormones also contribute to the pathophysiology of diseases such as locomotive syndrome (e.g., osteoporosis and sarcopenia) and hormone-related cancers including breast and prostate cancers. Hormone sensitivity is a critical factor for determining diagnosis and treatment of hormone-related cancers, thus hormone-native cancers are usually treated with endocrine therapy.

 Sex hormone-dependent transcriptional regulation and gene expression are our particular interests. We investigate these issues based on the integrated analysis of high-throughput sequencing and genomic information. We previously identified an estrogen-responsive gene TRIM25/Efp and showed that it is a potential poor prognostic factor for breast cancer patients. Efp belongs to TRIM protein family and functions as a ubiquitin ligase, which exerts the protein degradation of its substrates including a cell-cycle checkpoint 14-3-3 sigma in cancer. It is also notable that Efp is essential for RIG-I activation in innate immunity. We further investigate the roles of other TRIM proteins in hormone-dependent cancers and diseases.

 We recently discovered that another estrogen-responsive gene COX7RP is a mitochondrial supercomplex assembly-stimulating factor, which promotes supra-organization of the respiratory complexes. Gain-of-function of COX7RP could increase energy production in cells and improve exercise endurance in mice. We now investigate the relevance of mitochondrial supercomplex formation in aging and diseases.

 Non-coding RNAs including microRNAs and long non-coding RNAs related to sex hormones are another our interest. We also focus on the study of RNA binding proteins that play roles in epigenetic regulation, which often associates with cancer progression and acquired resistance to anti-cancer drugs. As a cancer model for cancer research, we generated patient-derived cancer cells (PDCs) that can survive for a long term in a 3D culture system. By inoculating PDCs into severe immunodeficient mice, we generated patient-derived xenografts (PDXs), whose pathological phenotypes are often close to those of clinical cancers. Using models of PDCs and PDXs, we will define new molecular mechanisms underlying advanced cancers and develop alternative options for prevention, diagnosis and treatment for the disease.

Fig.1.

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スタッフ
Staff
Visiting Professor Satoshi Inoue
Professor Kuniko Horie-Inoue
Assistant Professor Kazuhiro Ikeda
Assistant Wataru Satou
Project Researcher Sachiko Shiba
Post doctor Yuichi Mitobe
Graduate Student Hidetaka Kawabata, Kaori Iino, Masaya Hosokawa,
Takeshi Namekawa, Saya Nagasawa, Shuhei Kamada,
Yang Chiu Jung, Sachi Kitayama
Project Technical Assistant Tomoko Suzuki, Ayako Teramoto
テーマ Research Projects
Elucidation of molecular mechanisms of sex steroid hormones and their transcriptomic regulatory network cascades
1)
Systematic analysis of gene network of sex steroid hormone receptor targets and their transcriptional and epigenetic regulation
2)
Functional analysis of mitochondrial respiratory supercomplexes in metabolism, aging, and cancer
3)
Analysis of therapy-resistant characteristics of cancer stem-like cells by means of 3D culture and xenograft model of patient-derived cancer cells (PDCs and PDXs)
4)
Functional analysis of ubiquitin ligase TRIM family associated with aging and cancer
5)
Systematic identification and analysis of regulatory mechanisms in regard to genes associated with age-related diseases
links Links to Related Institutes
Research Society for Cancer 3-D Culture
文献 Selected Publications
Takayama KI, 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).
[PMID: 29686105]
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).
[PMID: 29362448]
Takayama KI, 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).
[PMID: 29379164 ]
Shiba S, Ikeda K, Horie-Inoue K, Nakayama A, Tanaka T, Inoue S. Deficiency of COX7RP, a mitochondrial supercomplex assembly promoting factor, lowers blood glucose level in mice. Sci Rep 7:7606,(2017). 7:7606,(2017).
[PMID: 28790391]
Takayama KI, 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).
[PMID: 28893982]
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).
[PMID: 25600070]
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).
[PMID: 26404510]
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 16:4:2147, (2013).
[PMID: 23857330]
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 12:1665-1680,(2013).
[PMID: 23644382]
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).
[PMID: 12075357]
 
   
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