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Yanming Wu, Zhao Zhang, Mauro E Cenciarini, Cecilia J Proietti, Matias F Amasino, Tao Hong, Mei Yang, Yiji Liao, Huai-Chin Chiang, Virginia Kaklamani, Rinath Jeselsohn, Ratna K Vadlamudi, Tim H-M Huang, Rong Li, Carmine De Angelis, Xiaoyong Fu, Patricia V Elizalde, Rachel Schiff, Myles Brown, Kexin Xu
Resistance to cancer treatment can be driven by epigenetic reprogramming of specific transcriptomes in favor of the refractory phenotypes. Here we discover that tamoxifen resistance in breast cancer is driven by a regulatory axis consisting of a master transcription factor, its cofactor and an epigenetic regulator. The oncogenic histone methyltransferase EZH2 conferred tamoxifen resistance by silencing the expression of the estrogen receptor α (ERα) cofactor GREB1. In clinical specimens, induction of DNA methylation of a particular CpG enriched region at the GREB1 promoter negatively correlated with GREB1 levels and cell sensitivity to endocrine agents...
December 6, 2017: Cancer Research
Huihui Li, Chunxiao Chang, Yuhong Shang, Ling Qiang, Baoxuan Zhang, Bing Bu, Guohua Ren, Lihua Song, Mao Shang, Jinming Yu
Colorectal cancer (CRC) ranks the fifth leading cause of cancer death in China. EZH2 is a member of Polycomb-group (PcG) family and associated with transcriptional repression and cancer development. In this study, we report the association between a missense variant in EZH2 and risk of CRC. Through a systematic selection of variants in EZH2, we identified rs2302427 in the exon region of EZH2 and genotyped this variant in 852 CRC patients and 1,303 healthy controls using Taqman genotyping assay. The association between this variant and CRC risk was calculated using logistic regression with adjustment of sex, age, smoking status and drinking status...
November 7, 2017: Oncotarget
Pei-Pei Kung, Patrick Bingham, Alexei Brooun, Michael R Collins, Ya-Li Deng, Dac M Dinh, Connie Fan, Ketan S Gajiwala, Rita Grantner, Hovhannes J Gukasyan, Wenyue Hu, Buwen Huang, Robert S Kania, Susan E Kephart, Cody T Krivacic, Robert A Kumpf, Penney Khamphavong, Manfred Kraus, Wei Liu, Karen A Maegley, Lisa Nguyen, Shijian Ren, Daniel Tyler Richter, Robert A Rollins, Neal W Sach, Shikhar Sharma, John Sherrill, Jillian E Spangler, Albert E Stewart, Scott C Sutton, Sean Uryu, Dominique Verhelle, Hui Wang, Shuiwang Wang, Martin Wythes, Shuibo Xin, Shinji Yamazaki, Huichun Zhu, Jinjiang Zhu, Luke Zehnder, Martin P Edwards
A new series of lactam-derived EZH2 inhibitors was designed via a ligand- and physicochemical property-based strategy to address metabolic stability and thermodynamic solubility issues associated with previous lead compound 1. The new inhibitors incorporated an sp3 hybridized carbon atom at the 7-position of the lactam moiety present in lead compound 1 as a replacement for a dimethylisoxazole group. This transformation enabled optimization of the physicochemical properties and potency compared to compound 1...
December 6, 2017: Journal of Medicinal Chemistry
Maria C Donaldson, Natalya Katanayeva, Elisa Oricchio
SESTRIN1 is a tumor suppressor in follicular lymphoma that controls mTORC1 activity and it is inactivated by chromosomal deletions or epigenetically silenced by mutant EZH2Y641X. Pharmacological inhibition of EZH2 promotes SESTRIN1 re-expression and it restores its tumor suppressive activity, suggesting the possibility to epigenetically control mTORC1 activity.
2017: Molecular & Cellular Oncology
Tingting Liu, Junzhong Zhang, Zhongqiu Chai, Gang Wang, Naiqiang Cui, Bing Zhou
EGb 761, the standard ginkgo biloba extract, is frequently prescribed in traditional Chinese medicine. Currently, there is no research focusing on its role in human colorectal cancer progression. In our study, we determined the anti-metastatic effect of EGb 761 on colorectal cancer cells and further explored the potential underlying regulatory mechanism. The cell migration and invasion assay indicated that EGb 761 treatment of colorectal cancer cells induced inhibition of cell migration and invasion ability in a concentration-dependent manner...
October 31, 2017: Oncotarget
Si Chen, Fan Yao, Qinghuan Xiao, Qiannan Liu, Yikun Yang, Xuejuan Li, Guanglie Jiang, Takayoshi Kuno, Yue Fang
Enhancer of zeste homologue 2 (EZH2), a catalytic subunit of polycomb repressive complex 2, is overexpressed in a number of different tumors including breast cancer, and serves important roles in cell cycle regulation, proliferation, apoptosis, tumorigenesis and drug resistance. However, it remains unclear whether EZH2 contributes to tamoxifen resistance in breast cancer. In the present study, the role of EZH2 in tamoxifen resistance in MCF‑7 cells was investigated. EZH2 was overexpressed in MCF‑7 tamoxifen‑resistant (MCF‑7 TamR) cells...
November 27, 2017: Molecular Medicine Reports
Huan Yu, Meng Ma, Junya Yan, Longwen Xu, Jiayi Yu, Jie Dai, Tianxiao Xu, Huan Tang, Xiaowen Wu, Siming Li, Bin Lian, Lili Mao, Zhihong Chi, Chuanliang Cui, Jun Guo, Yan Kong
BACKGROUND: Coexistence of enhancer of zeste homolog 2 (EZH2) and BRAF gene aberrations has been described in many cancer types. In this study, we aim to explore the coexistence status of BRAF V600E mutation and the copy number variation of EZH2 and explore the potential of this combination as a therapeutic target. METHODS: A total of 138 cases of melanoma samples harboring BRAF V600E mutation were included, and EZH2 copy numbers were examined by QuantiGenePlex DNA Assays...
December 4, 2017: Journal of Translational Medicine
Liying Chen, Gabriela Alexe, Neekesh V Dharia, Linda Ross, Amanda Balboni Iniguez, Amy Saur Conway, Emily Jue Wang, Veronica Veschi, Norris Lam, Jun Qi, W Clay Gustafson, Nicole Nasholm, Francisca Vazquez, Barbara A Weir, Glenn S Cowley, Levi D Ali, Sasha Pantel, Guozhi Jiang, William F Harrington, Yenarae Lee, Amy Goodale, Rakela Lubonja, John M Krill-Burger, Robin M Meyers, Aviad Tsherniak, David E Root, James E Bradner, Todd R Golub, Charles Wm Roberts, William C Hahn, William A Weiss, Carol J Thiele, Kimberly Stegmaier
Pharmacologically difficult targets, such as MYC transcription factors, represent a major challenge in cancer therapy. For the childhood cancer neuroblastoma, amplification of the oncogene MYCN is associated with high-risk disease and poor prognosis. Here, we deployed genome-scale CRISPR-Cas9 screening of MYCN-amplified neuroblastoma and found a preferential dependency on genes encoding the polycomb repressive complex 2 (PRC2) components EZH2, EED, and SUZ12. Genetic and pharmacological suppression of EZH2 inhibited neuroblastoma growth in vitro and in vivo...
December 4, 2017: Journal of Clinical Investigation
Ha Thi Thanh Pham, Barbara Maurer, Michaela Prchal-Murphy, Reinhard Grausenburger, Eva Grundschober, Tahereh Javaheri, Harini Nivarthi, Auke Boersma, Thomas Kolbe, Mohamed Elabd, Florian Halbritter, Jan Pencik, Zahra Kazemi, Florian Grebien, Markus Hengstschläger, Lukas Kenner, Stefan Kubicek, Matthias Farlik, Christoph Bock, Peter Valent, Mathias Müller, Thomas Rülicke, Veronika Sexl, Richard Moriggl
STAT5B is often mutated in hematopoietic malignancies. The most frequent STAT5B mutation, Asp642His (N642H), has been found in over 90 leukemia and lymphoma patients. Here, we used the Vav1 promoter to generate transgenic mouse models that expressed either human STAT5B or STAT5BN642H in the hematopoietic compartment. While STAT5B-expressing mice lacked a hematopoietic phenotype, the STAT5BN642H-expressing mice rapidly developed T cell neoplasms. Neoplasia manifested as transplantable CD8+ lymphoma or leukemia, indicating that the STAT5BN642H mutation drives cancer development...
December 4, 2017: Journal of Clinical Investigation
Nana Ni, Hao Song, Xiaopo Wang, Xiulian Xu, Yiqun Jiang, Jianfang Sun
Accumulating evidences have suggested that focally amplified lncRNA on chromosome 1 (FALEC) serves as an oncogenic long non-coding RNA (lncRNA) and has been identified to be dysregulated in various tumors. However, the expression, clinical values, and biological function of FALEC in melanoma are still unknown. In this study we detected the expression level of FALEC in tumor tissues and cell lines and measured the prognostic value of FALEC for melanoma patients and the biological effects of FALEC on melanoma cell proliferation, cell cycle, and apoptosis...
November 28, 2017: Biomedicine & Pharmacotherapy, Biomédecine & Pharmacothérapie
Yetao Xu, Yifan Lian, Yuanyuan Zhang, Shiyun Huang, Qing Zuo, Nana Yang, Yanzi Chen, Dan Wu, Lizhou Sun
Despite progress in diagnostics and treatment for preeclampsia, it remains the foremost cause of maternal and foetal perinatal morbidity and mortality worldwide. Over recent years, various lines of evidence have emphasized long non-coding RNAs (lncRNAs) which function as an innovative regulator of biological behaviour, as exemplified by proliferation, apoptosis and metastasis. However, the role of lncRNAs has not been well described in preeclampsia. Here, we identified a lncRNA, PVT1, whose expression was down-regulated in qRT-PCR analyses in severe preeclampsia...
November 29, 2017: Journal of Cellular and Molecular Medicine
Yicheng Long, Ben Bolanos, Lihu Gong, Wei Liu, Karen J Goodrich, Xin Yang, Siming Chen, Anne R Gooding, Karen A Maegley, Ketan S Gajiwala, Alexei Brooun, Thomas R Cech, Xin Liu
Polycomb repressive complex 2 (PRC2) is a key chromatin modifier responsible for methylation of lysine 27 in histone H3. PRC2 has been shown to interact with thousands of RNA species in vivo, but understanding the physiological function of RNA binding has been hampered by the lack of separation-of-function mutants. Here, we use comprehensive mutagenesis and hydrogen deuterium exchange mass spectrometry (HDX-MS) to identify critical residues for RNA interaction in PRC2 core complexes from Homo sapiens and Chaetomium thermophilum, for which crystal structures are known...
November 29, 2017: ELife
Enas R Abu-Zhayia, Samah W Awwad, Bella Ben-Oz, Hanan Khoury-Haddad, Nabieh Ayoub
Cells have evolved DNA damage response (DDR) to repair DNA lesions and thus preserving genomic stability and impeding carcinogenesis. DNA damage induction is accompanied by transient transcription repression. Here, we describe a previously unrecognized role of chromodomain Y-like (CDYL1) protein in fortifying double-strand break (DSB)-induced transcription repression and repair. We showed that CDYL1 is rapidly recruited to damaged euchromatic regions in a poly [ADP-ribose] polymerase 1 (PARP1)-dependent, but ataxia telangiectasia mutated (ATM)-independent, manner...
November 21, 2017: Journal of Molecular Cell Biology
Chang Yu, Binbin Ding, Xinyang Zhang, Xiaoran Deng, Kerong Deng, Ziyong Cheng, Bengang Xing, Dayong Jin, Ping'an Ma, Jun Lin
Resistance to platinum agents is challenging in cancer treatment with platinum drugs. Such resistant cells prevent effective platinum accumulation intracellular and alter cellular adaptations to survive from cytotoxicity by regulating corresponding proteins expression. Ideal therapeutics should combine resolution to these pump and non-pump relevant resistance of cancer cells to achieve high efficacy and low side effect. Fe3O4 nanocarrier loaded with drugs could enter cells in a more efficient endocytosis manner which circumvents pump-relevant drug resistance...
November 14, 2017: Biomaterials
João Lobo, Ângelo Rodrigues, Luís Antunes, Inês Graça, João Ramalho-Carvalho, Filipa Quintela Vieira, Ana Teresa Martins, Jorge Oliveira, Carmen Jerónimo, Rui Henrique
INTRODUCTION: Overtreatment is a major concern in patients with prostate cancer (PCa). Prognostic biomarkers discriminating indolent from aggressive disease in prostate biopsy are urgently needed. We aimed to evaluate the prognostic value of Ki67, EZH2, LSD1, and SMYD3 immunoexpression in diagnostic biopsies from a cohort of PCa patients with long term follow-up. MATERIALS AND METHODS: A series of 189 consecutive prostate biopsies diagnosed with PCa (1997-2001) in a cancer center was included in the study, with follow-up last updated in November 2016...
November 22, 2017: Urologic Oncology
Brian Lin, Julie H Coleman, Jesse N Peterson, Matthew J Zunitch, Woochan Jang, Daniel B Herrick, James E Schwob
Adult neurogenesis in the olfactory epithelium is often depicted as a unidirectional pathway during homeostasis and repair. We challenge the unidirectionality of this model by showing that epithelial injury unlocks the potential for Ascl1+ progenitors and Neurog1+ specified neuronal precursors to dedifferentiate into multipotent stem/progenitor cells that contribute significantly to tissue regeneration in the murine olfactory epithelium (OE). We characterize these dedifferentiating cells using several lineage-tracing strains and single-cell mRNA-seq, and we show that Sox2 is required for initiating dedifferentiation and that inhibition of Ezh2 promotes multipotent progenitor expansion...
November 20, 2017: Cell Stem Cell
Pingting Wang, Yanjing Li, Tingting Meng, Junjiang Zhang, Yuanyuan Wei, Zhaosong Meng, Yunfeng Lin, Dayong Liu, Lei Sui
OBJECTIVES: KDM6A has been demonstrated critical in the regulation of cell fates. However, whether KDM6A is involved in cartilage formation remains unclear. In this study, we investigated the role of KDM6A in chondrogenic differentiation of PDLSCs, as well as the underlying epigenetic mechanisms. METHODS: KDM6A shRNA was transfected into PDLSCs by lentivirus. The chondrogenic differentiation potential of PDLSCs was assessed by Alcian blue staining. Immunofluorescence was performed to demonstrate H3K27me3 and H3K4me3 levels during chondrogenesis...
November 23, 2017: Cell Proliferation
Jian Sun, Xin Tian, Sheng-Qiang Lu, Hai-Bo Hu
MicroRNA-26 (miR-26) has been reported to be connected with tumor progression. MicroRNA-4465 (miR-4465) was one member of miR-26 family, however, the role of miR-4465 in non-small cell lung cancer (NSCLC) was unknown. This study was aimed to explore the function of miR-4465 and investigate whether miR-4465 can be a potential target for treating human NSCLC. QRT-PCR was applied to evaluate the miR-4465 expression levels in NSCLC cells. Then, we demonstrated the role of miR-4465 in NSCLC cells biological characteristics through detecting proliferation, migration and invasion...
November 20, 2017: Biomedicine & Pharmacotherapy, Biomédecine & Pharmacothérapie
Mouhamed Idrissou, Marine Daures, Amani Ben Jemia, Gaëlle Judes, Khaldoun Rifaï, Frédérique Penault-Llorca, Yves-Jean Bignon, Laurent Guy, Dominique Bernard-Gallon
No abstract text is available yet for this article.
November 21, 2017: Omics: a Journal of Integrative Biology
Michael R Green
Follicular lymphoma (FL) is an indolent malignancy of germinal center B (GCB)-cells. Although the overall survival of FL patients has recently improved with the introduction of novel therapies, there is significant heterogeneity in patient outcome and a need for rationally designed therapeutic strategies that target disease biology. Next generation sequencing studies have identified chromatin modifying gene (CMG) mutations as a hallmark of FL, highlighting epigenetic modifiers as an attractive therapeutic target in this disease...
November 20, 2017: Blood
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