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Sze Chuen Cesar Wong, Moon Tong Cheung, Lewis Lai Yin Luk, Vivian Ha Man Lee, Pak Tat Chan, Hin Fung Andy Tsang, Evelyn Yin Kwan Wong, Vivian Weiwen Xue, Amanda Kit Ching Chan, John Kwok Cheung Chan
BACKGROUND: Cytokeratin 20-positive cells in lymph nodes from pN0 colorectal cancer (CRC) patients were detected previously by us. The aims of this study were to investigate which tumor metastasis-related genes were involved and their potential clinical significance. RESULTS: Fourteen of 84 (17%) genes were differentially expressed by at least 2-fold. Among them, 10 genes were up-regulated whereas 4 genes were down-regulated. Those differential expressed genes were validated in the second cohort of specimens...
January 23, 2018: Oncotarget
Chi-Wen Luo, Chun-Chieh Wu, Shu-Jyuan Chang, Tsung-Ming Chang, Tzu-Yi Chen, Chee-Yin Chai, Chia-Lo Chang, Ming-Feng Hou, Mei-Ren Pan
Triple-negative breast cancer (TNBC) is a subtype of cancer with aggressive behaviors (high recurrence and metastasis rate) and poor prognosis. Therefore, studying the determining factors that lead to malignant TNBCs is necessary to develop personalized therapy and improve survival rates. In this study, we first analyzed levels of chromodomain helicase DNA binding protein 4 (CHD4) in 60 TNBC patients by immunohistochemical staining. We then clarified the role of CHD4 in TNBC and non-TNBC cell lines. Our clinical data indicated that higher CHD4 expression is positively correlated with metastatic stage, tumor recurrence, and survival status...
January 3, 2018: Experimental Cell Research
Valeria Tomati, Emanuela Pesce, Emanuela Caci, Elvira Sondo, Paolo Scudieri, Monica Marini, Felice Amato, Giuseppe Castaldo, Roberto Ravazzolo, Luis J V Galietta, Nicoletta Pedemonte
In cystic fibrosis, deletion of phenylalanine 508 (F508del) in the cystic fibrosis transmembrane conductance regulator (CFTR) anion channel causes misfolding and premature degradation. One possible approach to reducing the detrimental health effects of cystic fibrosis could be the identification of proteins whose suppression rescues F508del-CFTR function in bronchial epithelial cells. However, searches for these potential targets have not yet been conducted, particularly in a relevant airway background using a functional readout...
January 26, 2018: Journal of Biological Chemistry
Jovylyn Gatchalian, Xiaodong Wang, Jinzen Ikebe, Khan L Cox, Adam H Tencer, Yi Zhang, Nathaniel L Burge, Luo Di, Matthew D Gibson, Catherine A Musselman, Michael G Poirier, Hidetoshi Kono, Jeffrey J Hayes, Tatiana G Kutateladze
Combinatorial polyvalent contacts of histone-binding domains or readers commonly mediate localization and activities of chromatin-associated proteins. A pair of readers, the PHD fingers of the protein CHD4, has been shown to bivalently recognize histone H3 tails. Here we describe a mechanism by which these linked but independent readers bind to the intact nucleosome core particle (NCP). Comprehensive NMR, chemical reactivity, molecular dynamics, and fluorescence analyses point to the critical roles of intra-nucleosomal histone-DNA interactions that reduce the accessibility of H3 tails in NCP, the nucleosomal DNA, and the linker between readers in modulating nucleosome- and/or histone-binding activities of the readers...
November 14, 2017: Nature Communications
Sabyasachi Sen, Sulagna Sanyal, Dushyant Kumar Srivastava, Dipak Dasgupta, Siddhartha Roy, Chandrima Das
Transcription Factor 19 (TCF19) has been reported as type 1 diabetes associated locus involved in maintenance of pancreatic β cells through a fine-tuned regulation of cell proliferation and apoptosis. TCF19 also exhibits genomic association with type 2 diabetes, although the precise molecular mechanism remains unknown. It harbours both a plant homeodomain (PHD) and a forkhead-associated domain (FHA) implicated in epigenetic recognition and gene regulation, a phenomenon that has remained unexplored. Here, we show that TCF19 selectively interacts with histone 3 lysine 4 trimethylation (H3K4Me3) through its PHD finger...
October 17, 2017: Journal of Biological Chemistry
Helen Hoffmeister, Andreas Fuchs, Fabian Erdel, Sophia Pinz, Regina Gröbner-Ferreira, Astrid Bruckmann, Rainer Deutzmann, Uwe Schwartz, Rodrigo Maldonado, Claudia Huber, Anne-Sarah Dendorfer, Karsten Rippe, Gernot Längst
CHD3 and CHD4 (Chromodomain Helicase DNA binding protein), two highly similar representatives of the Mi-2 subfamily of SF2 helicases, are coexpressed in many cell lines and tissues and have been reported to act as the motor subunit of the NuRD complex (nucleosome remodeling and deacetylase activities). Besides CHD proteins, NuRD contains several repressors like HDAC1/2, MTA2/3 and MBD2/3, arguing for a role as a transcriptional repressor. However, the subunit composition varies among cell- and tissue types and physiological conditions...
October 13, 2017: Nucleic Acids Research
Matthieu Le Gallo, Meghan L Rudd, Mary Ellen Urick, Nancy F Hansen, Maria J Merino, David G Mutch, Paul J Goodfellow, James C Mullikin, Daphne W Bell
BACKGROUND: Uterine carcinosarcomas (UCSs) are a rare but clinically aggressive form of cancer. They are biphasic tumors consisting of both epithelial and sarcomatous components. The majority of uterine carcinosarcomas are clonal, with the carcinomatous cells undergoing metaplasia to give rise to the sarcomatous component. The objective of the current study was to identify novel somatically mutated genes in UCSs. METHODS: We whole exome sequenced paired tumor and nontumor DNAs from 14 UCSs and orthogonally validated 464 somatic variants using Sanger sequencing...
January 1, 2018: Cancer
Ming-Feng Hou, Chi-Wen Luo, Tsung-Ming Chang, Wen-Chun Hung, Tzu-Yi Chen, Ya-Li Tsai, Chee-Yin Chai, Mei-Ren Pan
The Mi-2/nucleosome remodeling and deacetylase (NuRD) complex play a role in silencing gene expression. CHD4, the core component of the NuRD complex, which cooperates with histone deacetylase in reducing tumor suppressor genes (TSGs). To dissect the mechanisms underlying cancer promotion, we clarify the role of CHD4 in cyclin-dependent kinase inhibitor protein p21. Here, our data indicates that CHD4 deficiency impairs the recruitments of HDAC1 to the p21 promoter. ~ 300bp proximal promoter region is responsible for CHD4-HDAC1 axis-mediated p21 transcriptional activity...
October 15, 2017: Experimental Cell Research
Chun-Chieh Wu, Mei-Ren Pan, Yu-Ching Wei, Chih-Hung Lin, Sheau-Fang Yang, Hung-Pei Tsai, Chi-Wen Luo, Chee-Yin Chai
Cellular schwannoma is an uncommon variant of benign peripheral nerve sheath tumors, but is commonly misdiagnosed as malignant peripheral sheath tumor (MPNST). Conventional methods that are used to distinguish cellular schwannoma from MPNST include immunohistochemistry (IHC) staining. However, most markers cannot precisely differentiate these 2 tumor types, and thus identification of a better marker is needed to improve the accuracy of diagnosis. Here, we evaluate the use of chromodomain helicase DNA-binding protein 4 (CHD4) as a specific marker for cellular schwannoma by comparing CHD4 and S-100 IHC staining in 14 cellular schwannoma and 17 MPNST tissue samples...
May 25, 2017: Applied Immunohistochemistry & Molecular Morphology: AIMM
(no author information available yet)
CHD4 maintains epigenetic silencing of tumor suppressor genes to promote tumorigenesis.
May 19, 2017: Cancer Discovery
Limin Xia, Wenjie Huang, Marina Bellani, Michael M Seidman, Kaichun Wu, Daiming Fan, Yongzhan Nie, Yi Cai, Yang W Zhang, Li-Rong Yu, Huili Li, Cynthia A Zahnow, Wenbing Xie, Ray-Whay Chiu Yen, Feyruz V Rassool, Stephen B Baylin
An oncogenic role for CHD4, a NuRD component, is defined for initiating and supporting tumor suppressor gene (TSG) silencing in human colorectal cancer. CHD4 recruits repressive chromatin proteins to sites of DNA damage repair, including DNA methyltransferases where it imposes de novo DNA methylation. At TSGs, CHD4 retention helps maintain DNA hypermethylation-associated transcriptional silencing. CHD4 is recruited by the excision repair protein OGG1 for oxidative damage to interact with the damage-induced base 8-hydroxydeoxyguanosine (8-OHdG), while ZMYND8 recruits it to double-strand breaks...
May 8, 2017: Cancer Cell
Deokjae Lee, Jungeun An, Young-Un Park, Hungjiun Liaw, Roger Woodgate, Jun Hong Park, Kyungjae Myung
Many DNA repair proteins have additional functions other than their roles in DNA repair. In addition to catalyzing PCNA polyubiquitylation in response to the stalling of DNA replication, SHPRH has the additional function of facilitating rRNA transcription by localizing to the ribosomal DNA (rDNA) promoter in the nucleoli. SHPRH was recruited to the rDNA promoter using its plant homeodomain (PHD), which interacts with histone H3 when the fourth lysine of H3 is not trimethylated. SHPRH enrichment at the rDNA promoter was inhibited by cell starvation, by treatment with actinomycin D or rapamycin, or by depletion of CHD4...
April 25, 2017: Proceedings of the National Academy of Sciences of the United States of America
Ziwei Liang, Karen E Brown, Thomas Carroll, Benjamin Taylor, Isabel Ferreirós Vidal, Brian Hendrich, David Rueda, Amanda G Fisher, Matthias Merkenschlager
Turning genes on and off is essential for development and homeostasis, yet little is known about the sequence and causal role of chromatin state changes during the repression of active genes. This is surprising, as defective gene silencing underlies developmental abnormalities and disease. Here we delineate the sequence and functional contribution of transcriptional repression mechanisms at high temporal resolution. Inducible entry of the NuRD-interacting transcriptional regulator Ikaros into mouse pre-B cell nuclei triggered immediate binding to target gene promoters...
March 20, 2017: ELife
Haixin Zhao, Zhijun Han, Xinyuan Liu, Junjie Gu, Fan Tang, Gang Wei, Ying Jin
The unique properties of embryonic stem cells (ESCs), including unlimited self-renewal and pluripotent differentiation potential, are sustained by integrated genetic and epigenetic networks composed of transcriptional factors and epigenetic modulators. However, the molecular mechanisms underlying the function of these regulators are not fully elucidated. Chromodomain helicase DNA-binding protein 4 (Chd4), an ATPase subunit of the nucleosome remodeling and deacetylase (NuRD) complex, is highly expressed in ESCs...
May 19, 2017: Journal of Biological Chemistry
Maria A Pantaleo, Milena Urbini, Valentina Indio, Gloria Ravegnini, Margherita Nannini, Matilde De Luca, Giuseppe Tarantino, Sabrina Angelini, Alessandro Gronchi, Bruno Vincenzi, Giovanni Grignani, Chiara Colombo, Elena Fumagalli, Lidia Gatto, Maristella Saponara, Manuela Ianni, Paola Paterini, Donatella Santini, Maria Giulia Pirini, Claudio Ceccarelli, Annalisa Altimari, Elisa Gruppioni, Salvatore L Renne, Paola Collini, Silvia Stacchiotti, Giovanni Brandi, Paolo G Casali, Antonio D Pinna, Annalisa Astolfi, Guido Biasco
Quadruple wild-type (WT) gastrointestinal stromal tumors (GIST) is a genomic subgroup lacking KIT/PDGFRA/RAS pathways mutations, with an intact succinate dehydrogenase (SDH) complex. The aim of this work is to perform a wide comprehensive genomic study on quadruple WT GIST to improve the characterization of these patients. We selected 14 clinical cases of quadruple WT GIST, of which nine cases showed sufficient DNA quality for Whole Exome Sequencing (WES). NF1 alterations were identified directly by WES. Gene expression from Whole Transcriptome Sequencing (WTS) and miRNA profiling were performed using fresh-frozen, quadruple WT GIST tissue specimens and compared to SDH and KIT/PDGFRAmutant GIST...
January 27, 2017: Molecular Cancer Research: MCR
Pablo García-Sanz, Juan Carlos Triviño, Alba Mota, María Pérez López, Eva Colás, Alejandro Rojo-Sebastián, Ángel García, Sonia Gatius, María Ruiz, Jaime Prat, Rafael López-López, Miguel Abal, Antonio Gil-Moreno, Jaume Reventós, Xavier Matias-Guiu, Gema Moreno-Bueno
In developed countries, endometrial carcinoma is the most common cancer that affects the female genital tract. Endometrial carcinoma is divided into two main histological types, type I or endometrioid and type II or non-endometrioid, each of which have characteristic, although not exclusive, molecular alterations and mutational profiles. Nevertheless, information about the implication and relevance of some of these genes in this disease is lacking. We sought here to identify new recurrently mutated genes in endometrioid cancers that play a role in tumourigenesis and that influence the clinical outcome...
April 1, 2017: International Journal of Cancer. Journal International du Cancer
Justyna Nitarska, Jacob G Smith, William T Sherlock, Michele M G Hillege, Alexi Nott, William D Barshop, Ajay A Vashisht, James A Wohlschlegel, Richard Mitter, Antonella Riccio
Histone modifications and chromatin remodeling represent universal mechanisms by which cells adapt their transcriptional response to rapidly changing environmental conditions. Extensive chromatin remodeling takes place during neuronal development, allowing the transition of pluripotent cells into differentiated neurons. Here, we report that the NuRD complex, which couples ATP-dependent chromatin remodeling with histone deacetylase activity, regulates mouse brain development. Subunit exchange of CHDs, the core ATPase subunits of the NuRD complex, is required for distinct aspects of cortical development...
November 1, 2016: Cell Reports
Tao Nie, Xiaoyan Hui, Liufeng Mao, Baoming Nie, Kuai Li, Wei Sun, Xuefei Gao, Xiaofeng Tang, Yong Xu, Baishan Jiang, Zhengcao Tu, Peng Li, Ke Ding, Weiping Han, Shaoping Zhang, Aimin Xu, Sheng Ding, Pentao Liu, Adam Patterson, Garth Cooper, Donghai Wu
Harmine is a natural compound possessing insulin-sensitizing effect in db/db diabetic mice. However its effect on adipose tissue browning is unknown. Here we reveal that harmine antagonizes high fat diet-induced adiposity. Harmine-treated mice gained less weight on a high fat diet and displayed increased energy expenditure and adipose tissue thermogenesis. In vitro, harmine potently induced the expression of thermogenic genes in both brown and white adipocytes, which was largely abolished by inhibition of RAC1/MEK/ERK pathway...
November 2, 2016: Scientific Reports
Siming Zhao, Stefania Bellone, Salvatore Lopez, Durga Thakral, Carlton Schwab, Diana P English, Jonathan Black, Emiliano Cocco, Jungmin Choi, Luca Zammataro, Federica Predolini, Elena Bonazzoli, Mark Bi, Natalia Buza, Pei Hui, Serena Wong, Maysa Abu-Khalaf, Antonella Ravaggi, Eliana Bignotti, Elisabetta Bandiera, Chiara Romani, Paola Todeschini, Renata Tassi, Laura Zanotti, Franco Odicino, Sergio Pecorelli, Carla Donzelli, Laura Ardighieri, Fabio Facchetti, Marcella Falchetti, Dan-Arin Silasi, Elena Ratner, Masoud Azodi, Peter E Schwartz, Shrikant Mane, Roberto Angioli, Corrado Terranova, Charles Matthew Quick, Babak Edraki, Kaya Bilgüvar, Moses Lee, Murim Choi, Amy L Stiegler, Titus J Boggon, Joseph Schlessinger, Richard P Lifton, Alessandro D Santin
Carcinosarcomas (CSs) of the uterus and ovary are highly aggressive neoplasms containing both carcinomatous and sarcomatous elements. We analyzed the mutational landscape of 68 uterine and ovarian CSs by whole-exome sequencing. We also performed multiregion whole-exome sequencing comprising two carcinoma and sarcoma samples from six tumors to resolve their evolutionary histories. The results demonstrated that carcinomatous and sarcomatous elements derive from a common precursor having mutations typical of carcinomas...
October 25, 2016: Proceedings of the National Academy of Sciences of the United States of America
Carolina D'Alesio, Simona Punzi, Angelo Cicalese, Lorenzo Fornasari, Laura Furia, Laura Riva, Alessandro Carugo, Giuseppe Curigliano, Carmen Criscitiello, Giancarlo Pruneri, Pier Giuseppe Pelicci, Mario Faretta, Daniela Bossi, Luisa Lanfrancone
Epigenetic regulation plays an essential role in tumor development and epigenetic modifiers are considered optimal potential druggable candidates. In order to identify new breast cancer vulnerabilities and improve therapeutic chances for patients, we performed in vivo and in vitro shRNA screens in a human breast cancer cell model ( cell line) using epigenetic libraries. Among the genes identified in our screening, we deeply investigated the role of Chromodomain Helicase DNA binding Protein 4 (CHD4) in breast cancer tumorigenesis...
December 6, 2016: Oncotarget
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