Faculty Profiles - Hosono Yasuyuki

Papers - Hosono Yasuyuki

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A class of chemical compounds enhances clustering of muscle nicotinic acetylcholine receptor in cultured myogenic cells. International journal

Yuichi Miyairi, Bisei Ohkawara, Ayato Sato, Ryusuke Sawada, Hisao Ishii, Hiroyuki Tomita, Taro Inoue, Hiroaki Nakashima, Mikako Ito, Akio Masuda, Yasuyuki Hosono, Shiro Imagama, Kinji Ohno

Biochemical and biophysical research communications 731 150400 - 150400 2024.7

Language：English Publishing type：Research paper (scientific journal)

Neuromuscular signal transmission is affected in various diseases including myasthenia gravis, congenital myasthenic syndromes, and sarcopenia. We used an ATF2-luciferase system to monitor the phosphorylation of MuSK in HEK293 cells introduced with MUSK and LRP4 cDNAs to find novel chemical compounds that enhanced agrin-mediated acetylcholine receptor (AChR) clustering. Four compounds with similar chemical structures carrying benzene rings and heterocyclic rings increased the luciferase activities 8- to 30-folds, and two of them showed continuously graded dose dependence. The effects were higher than that of disulfiram, a clinically available aldehyde dehydrogenase inhibitor, which we identified to be the most competent preapproved drug to enhance ATF2-luciferase activity in the same assay system. In C2C12 myotubes, all the compounds increased the area, intensity, length, and number of AChR clusters. Three of the four compounds increased the phosphorylation of MuSK, but not of Dok7, JNK. ERK, or p38. Monitoring cell toxicity using the neurite elongation of NSC34 neuronal cells as a surrogate marker showed that all the compounds had no effects on the neurite elongation up to 1 μM. Extensive docking simulation and binding structure prediction of the four compounds with all available human proteins using AutoDock Vina and DiffDock showed that the four compounds were unlikely to directly bind to MuSK or Dok7, and the exact target remained unknown. The identified compounds are expected to serve as a seed to develop a novel therapeutic agent to treat defective NMJ signal transmission.

DOI： 10.1016/j.bbrc.2024.150400

Genetic architecture of alcohol consumption identified by a genotype-stratified GWAS and impact on esophageal cancer risk in Japanese people

Yuriko N. Koyanagi, Masahiro Nakatochi, Shinichi Namba, Isao Oze, Hadrien Charvat, Akira Narita, Takahisa Kawaguchi, Hiroaki Ikezaki, Asahi Hishida, Megumi Hara, Toshiro Takezaki, Teruhide Koyama, Yohko Nakamura, Sadao Suzuki, Sakurako Katsuura-Kamano, Kiyonori Kuriki, Yasuyuki Nakamura, Kenji Takeuchi, Atsushi Hozawa, Kengo Kinoshita, Yoichi Sutoh, Kozo Tanno, Atsushi Shimizu, Hidemi Ito, Yumiko Kasugai, Yukino Kawakatsu, Yukari Taniyama, Masahiro Tajika, Yasuhiro Shimizu, Etsuji Suzuki, Yasuyuki Hosono, Issei Imoto, Yasuharu Tabara, Meiko Takahashi, Kazuya Setoh, Koichi Matsuda, Shiori Nakano, Atsushi Goto, Ryoko Katagiri, Taiki Yamaji, Norie Sawada, Shoichiro Tsugane, Kenji Wakai, Masayuki Yamamoto, Makoto Sasaki, Fumihiko Matsuda, Yukinori Okada, Motoki Iwasaki, Paul Brennan, Keitaro Matsuo

Science Advances 10 ( 4 ) 2024.1

Publishing type：Research paper (scientific journal) Publisher：American Association for the Advancement of Science (AAAS)

An East Asian–specific variant on aldehyde dehydrogenase 2 ( ALDH2 rs671, G>A) is the major genetic determinant of alcohol consumption. We performed an rs671 genotype-stratified genome-wide association study meta-analysis of alcohol consumption in 175,672 Japanese individuals to explore gene-gene interactions with rs671 behind drinking behavior. The analysis identified three genome-wide significant loci ( GCKR , KLB , and ADH1B ) in wild-type homozygotes and six ( GCKR , ADH1B , ALDH1B1 , ALDH1A1 , ALDH2 , and GOT2 ) in heterozygotes, with five showing genome-wide significant interaction with rs671. Genetic correlation analyses revealed ancestry-specific genetic architecture in heterozygotes. Of the discovered loci, four ( GCKR , ADH1B , ALDH1A1 , and ALDH2 ) were suggested to interact with rs671 in the risk of esophageal cancer, a representative alcohol-related disease. Our results identify the genotype-specific genetic architecture of alcohol consumption and reveal its potential impact on alcohol-related disease risk.

DOI： 10.1126/sciadv.ade2780

Long non-coding RNA TILR constitutively represses TP53 and apoptosis in lung cancer. International journal

Mika Iwai, Taisuke Kajino, Masahiro Nakatochi, Kiyoshi Yanagisawa, Yasuyuki Hosono, Hisanori Isomura, Yukako Shimada, Motoshi Suzuki, Ayumu Taguchi, Takashi Takahashi

Oncogene 2022.12

Language：English Publishing type：Research paper (scientific journal)

Non-coding RNAs have an integral regulatory role in numerous functions related to lung cancer development. Here, we report identification of a novel lncRNA, termed TP53-inhibiting lncRNA (TILR), which was found to function as a constitutive negative regulator of p53 expression, including activation of downstream genes such as p21 and MDM2, and induction of apoptosis. A proteomic search for TILR-associated proteins revealed an association with PCBP2, while the mid-portion of TILR was found to be required for both PCBP2 and p53 mRNA binding. In addition, depletion of PCBP2 resulted in phenocopied effects of TILR silencing. TILR was also shown to suppress p53 expression in a post-transcriptional manner, as well as via a positive feedback loop involving p53 and Fanconi anemia pathway genes. Taken together, the present findings clearly demonstrate that TILR constitutively inhibits p53 expression in cooperation with PCBP2, thus maintaining p53 transcriptional activity at a level sufficiently low for avoidance of spurious apoptosis induction.

DOI： 10.1038/s41388-022-02546-w

Meclozine Attenuates the MARK Pathway in Mammalian Chondrocytes and Ameliorates FGF2-Induced Bone Hyperossification in Larval Zebrafish. International journal

Genta Takemoto, Masaki Matsushita, Takaaki Okamoto, Toshinari Ito, Yuki Matsuura, Chieko Takashima, Toyofumi Fengshi Chen-Yoshikawa, Hiromichi Ebi, Shiro Imagama, Hiroshi Kitoh, Kinji Ohno, Yasuyuki Hosono

Frontiers in cell and developmental biology 9 694018 - 694018 2021

Language：English Publishing type：Research paper (scientific journal)

Meclozine has been developed as an inhibitor of fibroblast growth factor receptor 3 (FGFR3) to treat achondroplasia (ACH). Extracellular signal regulated kinase (ERK) phosphorylation was attenuated by meclozine in FGF2-treated chondrocyte cell line, but the site of its action has not been elucidated. Although orally administered meclozine promoted longitudinal bone growth in a mouse model of ACH, its effect on craniofacial bone development during the early stage remains unknown. Herein, RNA-sequencing analysis was performed using murine chondrocytes from FGF2-treated cultured tibiae, which was significantly elongated by meclozine treatment. Gene set enrichment analysis demonstrated that FGF2 significantly increased the enrichment score of mitogen-activated protein kinase (MAPK) family signaling cascades in chondrocytes; however, meclozine reduced this enrichment. Next, we administered meclozine to FGF2-treated larval zebrafish from 8 h post-fertilization (hpf). We observed that FGF2 significantly increased the number of ossified vertebrae in larval zebrafish at 7 days post-fertilization (dpf), while meclozine delayed vertebral ossification in FGF2-induced zebrafish. Meclozine also reversed the FGF2-induced upregulation of ossified craniofacial bone area, including ceratohyal, hyomandibular, and quadrate. The current study provided additional evidence regarding the inhibitory effect of meclozine on the FGF2-induced upregulation of MAPK signaling in chondrocytes and FGF2-induced development of craniofacial and vertebral bones.

DOI： 10.3389/fcell.2021.694018

Genome-wide association meta-analysis identifies GP2 gene risk variants for pancreatic cancer. International journal

Yingsong Lin, Masahiro Nakatochi, Yasuyuki Hosono, Hidemi Ito, Yoichiro Kamatani, Akihito Inoko, Hiromi Sakamoto, Fumie Kinoshita, Yumiko Kobayashi, Hiroshi Ishii, Masato Ozaka, Takashi Sasaki, Masato Matsuyama, Naoki Sasahira, Manabu Morimoto, Satoshi Kobayashi, Taito Fukushima, Makoto Ueno, Shinichi Ohkawa, Naoto Egawa, Sawako Kuruma, Mitsuru Mori, Haruhisa Nakao, Yasushi Adachi, Masumi Okuda, Takako Osaki, Shigeru Kamiya, Chaochen Wang, Kazuo Hara, Yasuhiro Shimizu, Tatsuo Miyamoto, Yuko Hayashi, Hiromichi Ebi, Tomohiro Kohmoto, Issei Imoto, Yumiko Kasugai, Yoshinori Murakami, Masato Akiyama, Kazuyoshi Ishigaki, Koichi Matsuda, Makoto Hirata, Kazuaki Shimada, Takuji Okusaka, Takahisa Kawaguchi, Meiko Takahashi, Yoshiyuki Watanabe, Kiyonori Kuriki, Aya Kadota, Rieko Okada, Haruo Mikami, Toshiro Takezaki, Sadao Suzuki, Taiki Yamaji, Motoki Iwasaki, Norie Sawada, Atsushi Goto, Kengo Kinoshita, Nobuo Fuse, Fumiki Katsuoka, Atsushi Shimizu, Satoshi S Nishizuka, Kozo Tanno, Ken Suzuki, Yukinori Okada, Momoko Horikoshi, Toshimasa Yamauchi, Takashi Kadowaki, Herbert Yu, Jun Zhong, Laufey T Amundadottir, Yuichiro Doki, Hideshi Ishii, Hidetoshi Eguchi, David Bogumil, Christopher A Haiman, Loic Le Marchand, Masaki Mori, Harvey Risch, Veronica W Setiawan, Shoichiro Tsugane, Kenji Wakai, Teruhiko Yoshida, Fumihiko Matsuda, Michiaki Kubo, Shogo Kikuchi, Keitaro Matsuo

Nature communications 11 ( 1 ) 3175 - 3175 2020.6

Language：English Publishing type：Research paper (scientific journal)

Pancreatic cancer is the fourth leading cause of cancer-related deaths in Japan. To identify risk loci, we perform a meta-analysis of three genome-wide association studies comprising 2,039 pancreatic cancer patients and 32,592 controls in the Japanese population. Here, we identify 3 (13q12.2, 13q22.1, and 16p12.3) genome-wide significant loci (P < 5.0 × 10-8), of which 16p12.3 has not been reported in the Western population. The lead single nucleotide polymorphism (SNP) at 16p12.3 is rs78193826 (odds ratio = 1.46, 95% confidence interval = 1.29-1.66, P = 4.28 × 10-9), an Asian-specific, nonsynonymous glycoprotein 2 (GP2) gene variant. Associations between selected GP2 gene variants and pancreatic cancer are replicated in 10,822 additional cases and controls of East Asian origin. Functional analyses using cell lines provide supporting evidence of the effect of rs78193826 on KRAS activity. These findings suggest that GP2 gene variants are probably associated with pancreatic cancer susceptibility in populations of East Asian ancestry.

DOI： 10.1038/s41467-020-16711-w

PTEN Loss Mediates Clinical Cross-Resistance to CDK4/6 and PI3Kα Inhibitors in Breast Cancer. International journal

Carlotta Costa, Ye Wang, Amy Ly, Yasuyuki Hosono, Ellen Murchie, Charlotte S Walmsley, Tiffany Huynh, Christopher Healy, Rachel Peterson, Shogo Yanase, Charles T Jakubik, Laura E Henderson, Leah J Damon, Daria Timonina, Ioannis Sanidas, Christopher J Pinto, Mari Mino-Kenudson, James R Stone, Nicholas J Dyson, Leif W Ellisen, Aditya Bardia, Hiromichi Ebi, Cyril H Benes, Jeffrey A Engelman, Dejan Juric

Cancer discovery 10 ( 1 ) 72 - 85 2020.1

Language：English Publishing type：Research paper (scientific journal)

The combination of CDK4/6 inhibitors with antiestrogen therapies significantly improves clinical outcomes in ER-positive advanced breast cancer. To identify mechanisms of acquired resistance, we analyzed serial biopsies and rapid autopsies from patients treated with the combination of the CDK4/6 inhibitor ribociclib with letrozole. This study revealed that some resistant tumors acquired RB loss, whereas other tumors lost PTEN expression at the time of progression. In breast cancer cells, ablation of PTEN, through increased AKT activation, was sufficient to promote resistance to CDK4/6 inhibition in vitro and in vivo. Mechanistically, PTEN loss resulted in exclusion of p27 from the nucleus, leading to increased activation of both CDK4 and CDK2. Because PTEN loss also causes resistance to PI3Kα inhibitors, currently approved in the post-CDK4/6 setting, these findings provide critical insight into how this single genetic event may cause clinical cross-resistance to multiple targeted therapies in the same patient, with implications for optimal treatment-sequencing strategies. SIGNIFICANCE: Our analysis of serial biopsies uncovered RB and PTEN loss as mechanisms of acquired resistance to CDK4/6 inhibitors, utilized as first-line treatment for ER-positive advanced breast cancer. Importantly, these findings have near-term clinical relevance because PTEN loss also limits the efficacy of PI3Kα inhibitors currently approved in the post-CDK4/6 setting.This article is highlighted in the In This Issue feature, p. 1.

DOI： 10.1158/2159-8290.CD-18-0830

Evaluation of ALK Fusion Newly Identified in Colon Cancer by a Comprehensive Genomic Analysis Reviewed

Yasuyuki Hosono, Toshiki Masuishi, Seiichiro Mitani, Rui Yamaguchi, Seiichi Kato, Takayuki Yoshino, Hiromichi Ebi

JCO Precision Oncology ( 3 ) 1 - 5 2019.12

Increased Synthesis of MCL-1 Protein Underlies Initial Survival of EGFR-Mutant Lung Cancer to EGFR Inhibitors and Provides a Novel Drug Target. International journal

Kyung-A Song, Yasuyuki Hosono, Crystal Turner, Sheeba Jacob, Timothy L Lochmann, Yoshiko Murakami, Neha U Patel, Jungoh Ham, Bin Hu, Krista M Powell, Colin M Coon, Brad E Windle, Yuko Oya, Jennifer E Koblinski, Hisashi Harada, Joel D Leverson, Andrew J Souers, Aaron N Hata, Sosipatros Boikos, Yasushi Yatabe, Hiromichi Ebi, Anthony C Faber

Clinical cancer research : an official journal of the American Association for Cancer Research 24 ( 22 ) 5658 - 5672 2018.11

Language：English Publishing type：Research paper (scientific journal)

Purpose: EGFR inhibitors (EGFRi) are effective against EGFR-mutant lung cancers. The efficacy of these drugs, however, is mitigated by the outgrowth of resistant cells, most often driven by a secondary acquired mutation in EGFR, T790M We recently demonstrated that T790M can arise de novo during treatment; it follows that one potential therapeutic strategy to thwart resistance would be identifying and eliminating these cells [referred to as drug-tolerant cells (DTC)] prior to acquiring secondary mutations like T790MExperimental Design: We have developed DTCs to EGFRi in EGFR-mutant lung cancer cell lines. Subsequent analyses of DTCs included RNA-seq, high-content microscopy, and protein translational assays. Based on these results, we tested the ability of MCL-1 BH3 mimetics to combine with EGFR inhibitors to eliminate DTCs and shrink EGFR-mutant lung cancer tumors in vivoResults: We demonstrate surviving EGFR-mutant lung cancer cells upregulate the antiapoptotic protein MCL-1 in response to short-term EGFRi treatment. Mechanistically, DTCs undergo a protein biosynthesis enrichment resulting in increased mTORC1-mediated mRNA translation of MCL-1, revealing a novel mechanism in which lung cancer cells adapt to short-term pressures of apoptosis-inducing kinase inhibitors. Moreover, MCL-1 is a key molecule governing the emergence of early EGFR-mutant DTCs to EGFRi, and we demonstrate it can be effectively cotargeted with clinically emerging MCL-1 inhibitors both in vitro and in vivoConclusions: Altogether, these data reveal that this novel therapeutic combination may delay the acquisition of secondary mutations, therefore prolonging therapy efficacy. Clin Cancer Res; 24(22); 5658-72. ©2018 AACR.

DOI： 10.1158/1078-0432.CCR-18-0304

Analysis of the androgen receptor-regulated lncRNA landscape identifies a role for ARLNC1 in prostate cancer progression. International journal

Yajia Zhang, Sethuramasundaram Pitchiaya, Marcin Cieślik, Yashar S Niknafs, Jean C-Y Tien, Yasuyuki Hosono, Matthew K Iyer, Sahr Yazdani, Shruthi Subramaniam, Sudhanshu K Shukla, Xia Jiang, Lisha Wang, Tzu-Ying Liu, Michael Uhl, Alexander R Gawronski, Yuanyuan Qiao, Lanbo Xiao, Saravana M Dhanasekaran, Kristin M Juckette, Lakshmi P Kunju, Xuhong Cao, Utsav Patel, Mona Batish, Girish C Shukla, Michelle T Paulsen, Mats Ljungman, Hui Jiang, Rohit Mehra, Rolf Backofen, Cenk S Sahinalp, Susan M Freier, Andrew T Watt, Shuling Guo, John T Wei, Felix Y Feng, Rohit Malik, Arul M Chinnaiyan

Nature genetics 50 ( 6 ) 814 - 824 2018.6

Language：English Publishing type：Research paper (scientific journal)

The androgen receptor (AR) plays a critical role in the development of the normal prostate as well as prostate cancer. Using an integrative transcriptomic analysis of prostate cancer cell lines and tissues, we identified ARLNC1 (AR-regulated long noncoding RNA 1) as an important long noncoding RNA that is strongly associated with AR signaling in prostate cancer progression. Not only was ARLNC1 induced by the AR protein, but ARLNC1 stabilized the AR transcript via RNA-RNA interaction. ARLNC1 knockdown suppressed AR expression, global AR signaling and prostate cancer growth in vitro and in vivo. Taken together, these data support a role for ARLNC1 in maintaining a positive feedback loop that potentiates AR signaling during prostate cancer progression and identify ARLNC1 as a novel therapeutic target.

DOI： 10.1038/s41588-018-0120-1

Oncogenic Role of THOR, a Conserved Cancer/Testis Long Non-coding RNA. International journal

Yasuyuki Hosono, Yashar S Niknafs, John R Prensner, Matthew K Iyer, Saravana M Dhanasekaran, Rohit Mehra, Sethuramasundaram Pitchiaya, Jean Tien, June Escara-Wilke, Anton Poliakov, Shih-Chun Chu, Sahal Saleh, Keerthana Sankar, Fengyun Su, Shuling Guo, Yuanyuan Qiao, Susan M Freier, Huynh-Hoa Bui, Xuhong Cao, Rohit Malik, Timothy M Johnson, David G Beer, Felix Y Feng, Weibin Zhou, Arul M Chinnaiyan

Cell 171 ( 7 ) 1559 - 1572 2017.12

Language：English Publishing type：Research paper (scientific journal)

Large-scale transcriptome sequencing efforts have vastly expanded the catalog of long non-coding RNAs (lncRNAs) with varying evolutionary conservation, lineage expression, and cancer specificity. Here, we functionally characterize a novel ultraconserved lncRNA, THOR (ENSG00000226856), which exhibits expression exclusively in testis and a broad range of human cancers. THOR knockdown and overexpression in multiple cell lines and animal models alters cell or tumor growth supporting an oncogenic role. We discovered a conserved interaction of THOR with IGF2BP1 and show that THOR contributes to the mRNA stabilization activities of IGF2BP1. Notably, transgenic THOR knockout produced fertilization defects in zebrafish and also conferred a resistance to melanoma onset. Likewise, ectopic expression of human THOR in zebrafish accelerated the onset of melanoma. THOR represents a novel class of functionally important cancer/testis lncRNAs whose structure and function have undergone positive evolutionary selection.

DOI： 10.1016/j.cell.2017.11.040

Inactivating mutations and hypermethylation of the NKX2-1/TTF-1 gene in non-terminal respiratory unit-type lung adenocarcinomas. International journal

Daisuke Matsubara, Manabu Soda, Taichiro Yoshimoto, Yusuke Amano, Yuji Sakuma, Azusa Yamato, Toshihide Ueno, Shinya Kojima, Tomoki Shibano, Yasuyuki Hosono, Masahito Kawazu, Yoshihiro Yamashita, Shunsuke Endo, Koichi Hagiwara, Masashi Fukayama, Takashi Takahashi, Hiroyuki Mano, Toshiro Niki

Cancer science 108 ( 9 ) 1888 - 1896 2017.9

Language：English Publishing type：Research paper (scientific journal)

The major driver mutations of lung cancer, EGFR mutations and EML4-ALK fusion, are mainly detected in terminal respiratory unit (TRU)-type lung adenocarcinomas, which typically show lepidic and/or papillary patterns, but are rarely associated with a solid or invasive mucinous morphology. In order to elucidate the key genetic events in non-TRU-type lung cancer, we carried out whole-exome sequencing on 43 non-TRU-type lung adenocarcinomas based on morphology (17 acinar, nine solid, and two enteric adenocarcinomas, and 15 adenocarcinomas with a mucinous morphology). Our analysis identified mutations in TP53 (16/43, 37.2%), KRAS (13/43, 30.2%), and NKX2-1/TTF-1 (7/43; 16.3%) as the top three significantly mutated genes, while the EGFR mutation was rare (1/43, 2.3%) in this cohort. Eight NKX2-1/TTF-1 mutations (five frameshift, two nonsense, and one missense) were identified, with one case harboring two distinct NKX2-1/TTF-1 mutations (one missense and one frameshift). Functional assays with the NK2 homeobox 1 (NKX2-1)/thyroid transcription factor 1 (TTF-1) mutants revealed that none of them retain the activity as a transcriptional factor. Histologically, invasive mucinous adenocarcinomas accounted for most of the NKX2-1/TTF-1 mutations (five cases), as well as one enteric and one acinar adenocarcinoma. Immunohistochemistry showed that the cohort was largely divided into TTF-1-postive/hepatocyte nuclear factor 4-α (HNF4-α)-negative and TTF-1-negative/HNF4-α-positive groups. NKX2-1/TTF-1 mutations were exclusively found in the latter, in which the gastrointestinal markers, mucin 5AC and cytokeratin 20, were frequently expressed. Bisulfite sequencing revealed that the NKX2-1/TTF-1 gene body was highly methylated in NKX2-1/TTF-1-negative cases, including those without the NKX2-1/TTF-1 mutations. The genetic or epigenetic inactivation of NKX2-1/TTF-1 may play an essential role in the development and aberrant differentiation of non-TRU-type lung adenocarcinomas.

DOI： 10.1111/cas.13313

The lncRNA landscape of breast cancer reveals a role for DSCAM-AS1 in breast cancer progression. International journal

Yashar S Niknafs, Sumin Han, Teng Ma, Corey Speers, Chao Zhang, Kari Wilder-Romans, Matthew K Iyer, Sethuramasundaram Pitchiaya, Rohit Malik, Yasuyuki Hosono, John R Prensner, Anton Poliakov, Udit Singhal, Lanbo Xiao, Steven Kregel, Ronald F Siebenaler, Shuang G Zhao, Michael Uhl, Alexander Gawronski, Daniel F Hayes, Lori J Pierce, Xuhong Cao, Colin Collins, Rolf Backofen, Cenk S Sahinalp, James M Rae, Arul M Chinnaiyan, Felix Y Feng

Nature communications 7 12791 - 12791 2016.9

Language：English Publishing type：Research paper (scientific journal)

Molecular classification of cancers into subtypes has resulted in an advance in our understanding of tumour biology and treatment response across multiple tumour types. However, to date, cancer profiling has largely focused on protein-coding genes, which comprise <1% of the genome. Here we leverage a compendium of 58,648 long noncoding RNAs (lncRNAs) to subtype 947 breast cancer samples. We show that lncRNA-based profiling categorizes breast tumours by their known molecular subtypes in breast cancer. We identify a cohort of breast cancer-associated and oestrogen-regulated lncRNAs, and investigate the role of the top prioritized oestrogen receptor (ER)-regulated lncRNA, DSCAM-AS1. We demonstrate that DSCAM-AS1 mediates tumour progression and tamoxifen resistance and identify hnRNPL as an interacting protein involved in the mechanism of DSCAM-AS1 action. By highlighting the role of DSCAM-AS1 in breast cancer biology and treatment resistance, this study provides insight into the potential clinical implications of lncRNAs in breast cancer.

DOI： 10.1038/ncomms12791

Blood-borne miRNA profile-based diagnostic classifier for lung adenocarcinoma. International journal

Mei Chee Tai, Kiyoshi Yanagisawa, Masahiro Nakatochi, Naoe Hotta, Yasuyuki Hosono, Koji Kawaguchi, Mariko Naito, Hiroyuki Taniguchi, Kenji Wakai, Kohei Yokoi, Takashi Takahashi

Scientific reports 6 31389 - 31389 2016.8

Language：English Publishing type：Research paper (scientific journal)

Accumulated evidence indicates that various types of miRNA are aberrantly expressed in lung cancer and secreted into the bloodstream. For this study, we constructed a serum diagnostic classifier based on detailed bioinformatics analysis of miRNA profiles from a training cohort of 143 lung adenocarcinoma patients and 49 healthy subjects, resulting in a 20 miRNA-based classifier. Validation performed with an independent cohort of samples from lung adenocarcinoma patients (n = 110), healthy subjects (n = 52), and benign pulmonary disease patients (n = 47) showed a sensitivity of 89.1% and specificity of 94.9%, with an area under the curve value of 0.958. Notably, 90.8% of Stage I lung adenocarcinoma cases were correctly diagnosed. Interestingly, this classifier also detected squamous and large cell lung carcinoma cases at relatively high rates (70.4% and 70.0%, respectively), which appears to be consistent with organ site-dependent miRNA expression in cancer tissues. In contrast, we observed significantly lower rates (0-35%) using samples from 96 cases of cancer in other major organs, with breast cancer the lowest. These findings warrant a future study to realize its clinical application as a part of diagnostic procedures for lung cancers, for which early detection and surgical removal is presently the only hope for eventual cure.

DOI： 10.1038/srep31389

KRAS Engages AGO2 to Enhance Cellular Transformation. International journal

Sunita Shankar, Sethuramasundaram Pitchiaya, Rohit Malik, Vishal Kothari, Yasuyuki Hosono, Anastasia K Yocum, Harika Gundlapalli, Yasmine White, Ari Firestone, Xuhong Cao, Saravana M Dhanasekaran, Jeanne A Stuckey, Gideon Bollag, Kevin Shannon, Nils G Walter, Chandan Kumar-Sinha, Arul M Chinnaiyan

Cell reports 14 ( 6 ) 1448 - 1461 2016.2

Language：English Publishing type：Research paper (scientific journal)

Oncogenic mutations in RAS provide a compelling yet intractable therapeutic target. Using co-immunoprecipitation mass spectrometry, we uncovered an interaction between RAS and Argonaute 2 (AGO2). Endogenously, RAS and AGO2 co-sediment and co-localize in the endoplasmic reticulum. The AGO2 N-terminal domain directly binds the Switch II region of KRAS, agnostic of nucleotide (GDP/GTP) binding. Functionally, AGO2 knockdown attenuates cell proliferation in mutant KRAS-dependent cells and AGO2 overexpression enhances KRAS(G12V)-mediated transformation. Using AGO2-/- cells, we demonstrate that the RAS-AGO2 interaction is required for maximal mutant KRAS expression and cellular transformation. Mechanistically, oncogenic KRAS attenuates AGO2-mediated gene silencing. Overall, the functional interaction with AGO2 extends KRAS function beyond its canonical role in signaling.

DOI： 10.1016/j.celrep.2016.01.034

The landscape of long noncoding RNAs in the human transcriptome. International journal

Matthew K Iyer, Yashar S Niknafs, Rohit Malik, Udit Singhal, Anirban Sahu, Yasuyuki Hosono, Terrence R Barrette, John R Prensner, Joseph R Evans, Shuang Zhao, Anton Poliakov, Xuhong Cao, Saravana M Dhanasekaran, Yi-Mi Wu, Dan R Robinson, David G Beer, Felix Y Feng, Hariharan K Iyer, Arul M Chinnaiyan

Nature genetics 47 ( 3 ) 199 - 208 2015.3

Language：English Publishing type：Research paper (scientific journal)

Long noncoding RNAs (lncRNAs) are emerging as important regulators of tissue physiology and disease processes including cancer. To delineate genome-wide lncRNA expression, we curated 7,256 RNA sequencing (RNA-seq) libraries from tumors, normal tissues and cell lines comprising over 43 Tb of sequence from 25 independent studies. We applied ab initio assembly methodology to this data set, yielding a consensus human transcriptome of 91,013 expressed genes. Over 68% (58,648) of genes were classified as lncRNAs, of which 79% were previously unannotated. About 1% (597) of the lncRNAs harbored ultraconserved elements, and 7% (3,900) overlapped disease-associated SNPs. To prioritize lineage-specific, disease-associated lncRNA expression, we employed non-parametric differential expression testing and nominated 7,942 lineage- or cancer-associated lncRNA genes. The lncRNA landscape characterized here may shed light on normal biology and cancer pathogenesis and may be valuable for future biomarker development.

DOI： 10.1038/ng.3192

NKX2-1/TTF-1: an enigmatic oncogene that functions as a double-edged sword for cancer cell survival and progression. International journal

Tomoya Yamaguchi, Yasuyuki Hosono, Kiyoshi Yanagisawa, Takashi Takahashi

Cancer cell 23 ( 6 ) 718 - 23 2013.6

Language：English Publishing type：Research paper (scientific journal)

Emerging evidence indicates that NKX2-1, a homeobox-containing transcription factor also known as TTF-1, plays a role as a "lineage-survival" oncogene in lung adenocarcinomas. In T cell acute lymphoblastic leukemia, gene rearrangements lead to aberrant expression of NKX2-1/TTF-1. Despite accumulating evidence supporting its oncogenic role, it has become apparent that NKX2-1/TTF-1 expression also has biological and clinical functions in the opposite direction that act against tumor progression. Herein, we review recent findings showing these enigmatic double-edged characteristics, with special attention given to the roles of NKX2-1/TTF-1 in lung development and carcinogenesis.

DOI： 10.1016/j.ccr.2013.04.002

MYBPH inhibits NM IIA assembly via direct interaction with NMHC IIA and reduces cell motility. International journal

Yasuyuki Hosono, Jiro Usukura, Tomoya Yamaguchi, Kiyoshi Yanagisawa, Motoshi Suzuki, Takashi Takahashi

Biochemical and biophysical research communications 428 ( 1 ) 173 - 8 2012.11

Language：English Publishing type：Research paper (scientific journal)

Actomyosin filament assembly is a critical step in tumor cell migration. We previously found that myosin binding protein H (MYBPH) is directly transactivated by the TTF-1 lineage-survival oncogene in lung adenocarcinomas and inhibits phosphorylation of the myosin regulatory light chain (RLC) of non-muscle myosin IIA (NM IIA) via direct interaction with Rho kinase 1 (ROCK1). Here, we report that MYBPH also directly interacts with an additional molecule, non-muscle myosin heavy chain IIA (NMHC IIA), which was found to occur between MYBPH and the rod portion of NMHC IIA. MYBPH inhibited NMHC IIA assembly and reduced cell motility. Conversely, siMYBPH-induced increased motility was partially, yet significantly, suppressed by blebbistatin, a non-muscle myosin II inhibitor, while more profound effects were attained by combined treatment with siROCK1 and blebbistatin. Electron microscopy observations showed well-ordered paracrystals of NMHC IIA reflecting an assembled state, which were significantly less frequently observed in the presence of MYBPH. Furthermore, an in vitro sedimentation assay showed that a greater amount of NMHC IIA was in an unassembled state in the presence of MYBPH. Interestingly, treatment with a ROCK inhibitor that impairs transition of NM IIA from an assembly-incompetent to assembly-competent state reduced the interaction between MYBPH and NMHC IIA, suggesting that MYBPH has higher affinity to assembly-competent NM IIA. These results suggest that MYBPH inhibits RLC and NMHC IIA, independent components of NM IIA, and negatively regulates actomyosin organization at 2 distinct steps, resulting in firm inhibition of NM IIA assembly.

DOI： 10.1016/j.bbrc.2012.10.036

NKX2-1/TITF1/TTF-1-Induced ROR1 is required to sustain EGFR survival signaling in lung adenocarcinoma. International journal

Tomoya Yamaguchi, Kiyoshi Yanagisawa, Ryoji Sugiyama, Yasuyuki Hosono, Yukako Shimada, Chinatsu Arima, Seiichi Kato, Shuta Tomida, Motoshi Suzuki, Hirotaka Osada, Takashi Takahashi

Cancer cell 21 ( 3 ) 348 - 61 2012.3

Language：English Publishing type：Research paper (scientific journal)

We and others previously identified NKX2-1, also known as TITF1 and TTF-1, as a lineage-survival oncogene in lung adenocarcinomas. Here we show that NKX2-1 induces the expression of the receptor tyrosine kinase-like orphan receptor 1 (ROR1), which in turn sustains a favorable balance between prosurvival PI3K-AKT and pro-apoptotic p38 signaling, in part through ROR1 kinase-dependent c-Src activation, as well as kinase activity-independent sustainment of the EGFR-ERBB3 association, ERBB3 phosphorylation, and consequential PI3K activation. Notably, ROR1 knockdown effectively inhibited lung adenocarcinoma cell lines, irrespective of their EGFR status, including those with resistance to the EGFR tyrosine kinase inhibitor gefitinib. Our findings thus identify ROR1 as an "Achilles' heel" in lung adenocarcinoma, warranting future development of therapeutic strategies for this devastating cancer.

DOI： 10.1016/j.ccr.2012.02.008

MYBPH, a transcriptional target of TTF-1, inhibits ROCK1, and reduces cell motility and metastasis. International journal

Yasuyuki Hosono, Tomoya Yamaguchi, Eri Mizutani, Kiyoshi Yanagisawa, Chinatsu Arima, Shuta Tomida, Yukako Shimada, Michiyo Hiraoka, Seiichi Kato, Kohei Yokoi, Motoshi Suzuki, Takashi Takahashi

The EMBO journal 31 ( 2 ) 481 - 93 2012.1

Language：English Publishing type：Research paper (scientific journal)

Cell migration driven by actomyosin filament assembly is a critical step in tumour invasion and metastasis. Herein, we report identification of myosin binding protein H (MYBPH) as a transcriptional target of TTF-1 (also known as NKX2-1 and TITF1), a master regulator of lung development that also plays a role as a lineage-survival oncogene in lung adenocarcinoma development. MYBPH inhibited assembly competence-conferring phosphorylation of the myosin regulatory light chain (RLC) as well as activating phosphorylation of LIM domain kinase (LIMK), unexpectedly through its direct physical interaction with Rho kinase 1 (ROCK1) rather than with RLC. Consequently, MYBPH inhibited ROCK1 and negatively regulated actomyosin organization, which in turn reduced single cell motility and increased collective cell migration, resulting in decreased cancer invasion and metastasis. Finally, we also show that MYBPH is epigenetically inactivated by promoter DNA methylation in a fraction of TTF-1-positive lung adenocarcinomas, which appears to be in accordance with its deleterious functions in lung adenocarcinoma invasion and metastasis, as well as with the paradoxical association of TTF-1 expression with favourable prognosis in lung adenocarcinoma patients.

DOI： 10.1038/emboj.2011.416

A novel network profiling analysis reveals system changes in epithelial-mesenchymal transition. International journal

Teppei Shimamura, Seiya Imoto, Yukako Shimada, Yasuyuki Hosono, Atsushi Niida, Masao Nagasaki, Rui Yamaguchi, Takashi Takahashi, Satoru Miyano

PloS one 6 ( 6 ) e20804 2011

Language：English Publishing type：Research paper (scientific journal)

Patient-specific analysis of molecular networks is a promising strategy for making individual risk predictions and treatment decisions in cancer therapy. Although systems biology allows the gene network of a cell to be reconstructed from clinical gene expression data, traditional methods, such as bayesian networks, only provide an averaged network for all samples. Therefore, these methods cannot reveal patient-specific differences in molecular networks during cancer progression. In this study, we developed a novel statistical method called NetworkProfiler, which infers patient-specific gene regulatory networks for a specific clinical characteristic, such as cancer progression, from gene expression data of cancer patients. We applied NetworkProfiler to microarray gene expression data from 762 cancer cell lines and extracted the system changes that were related to the epithelial-mesenchymal transition (EMT). Out of 1732 possible regulators of E-cadherin, a cell adhesion molecule that modulates the EMT, NetworkProfiler, identified 25 candidate regulators, of which about half have been experimentally verified in the literature. In addition, we used NetworkProfiler to predict EMT-dependent master regulators that enhanced cell adhesion, migration, invasion, and metastasis. In order to further evaluate the performance of NetworkProfiler, we selected Krueppel-like factor 5 (KLF5) from a list of the remaining candidate regulators of E-cadherin and conducted in vitro validation experiments. As a result, we found that knockdown of KLF5 by siRNA significantly decreased E-cadherin expression and induced morphological changes characteristic of EMT. In addition, in vitro experiments of a novel candidate EMT-related microRNA, miR-100, confirmed the involvement of miR-100 in several EMT-related aspects, which was consistent with the predictions obtained by NetworkProfiler.

DOI： 10.1371/journal.pone.0020804

Counterbalance between RB inactivation and miR-17-92 overexpression in reactive oxygen species and DNA damage induction in lung cancers. International journal

H Ebi, T Sato, N Sugito, Y Hosono, Y Yatabe, Y Matsuyama, T Yamaguchi, H Osada, M Suzuki, T Takahashi

Oncogene 28 ( 38 ) 3371 - 9 2009.9

Language：English Publishing type：Research paper (scientific journal)

Small-cell lung cancer (SCLC) is a highly aggressive disease that exhibits rapid growth and genetic instability. We found earlier frequent overexpression of the miR-17-92 microRNA cluster, and showed that SCLC cells were addicted to continued expressions of miR-17-5p and miR-20a, major components of this microRNA cluster. In this study, we identified the frequent presence of constitutively phosphorylated H2AX (gamma-H2AX), which reflects continuing DNA damage, preferentially in SCLC. Knockdown of RB induced gamma-H2AX foci formation in non-small cell lung cancer (NSCLC) cells with wild-type RB, in association with growth inhibition and reactive oxygen species (ROS) generation, which was canceled by overexpression of miR-17-92. Conversely, induction of gamma-H2AX was observed in a miR-17-92-overexpressing SCLC cell line with miR-20a antisense oligonucleotides. These findings suggest that miR-17-92 overexpression may serve as a fine-tuning influence to counterbalance the generation of DNA damage in RB-inactivated SCLC cells, thus reducing excessive DNA damage to a tolerable level and consequently leading to genetic instability. Therefore, miR-17-92 may be an excellent therapeutic target candidate to elicit excessive DNA damage in combination with DNA-damaging chemotherapeutics.

DOI： 10.1038/onc.2009.201

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