title: LncRNA HOXA11-AS Promotes Proliferation and Invasion of Gastric Cancer by Scaffolding the Chromatin Modification Factors PRC2, LSD1, and DNMT1.
abstract: Long noncoding RNAs (lncRNA) have been implicated in human cancer but their mechanisms of action are mainly undocumented. In this study, we investigated lncRNA alterations that contribute to gastric cancer through an analysis of The Cancer Genome Atlas RNA sequencing data and other publicly available microarray data. Here we report the gastric cancer-associated lncRNA HOXA11-AS as a key regulator of gastric cancer development and progression. Patients with high HOXA11-AS expression had a shorter survival and poorer prognosis. In vitro and in vivo assays of HOXA11-AS alterations revealed a complex integrated phenotype affecting cell growth, migration, invasion, and apoptosis. Strikingly, high-throughput sequencing analysis after HOXA11-AS silencing highlighted alterations in cell proliferation and cell-cell adhesion pathways. Mechanistically, EZH2 along with the histone demethylase LSD1 or DNMT1 were recruited by HOXA11-AS, which functioned as a scaffold. HOXA11-AS also functioned as a molecular sponge for miR-1297, antagonizing its ability to repress EZH2 protein translation. In addition, we found that E2F1 was involved in HOXA11-AS activation in gastric cancer cells. Taken together, our findings support a model in which the EZH2/HOXA11-AS/LSD1 complex and HOXA11-AS/miR-1297/EZH2 cross-talk serve as critical effectors in gastric cancer tumorigenesis and progression, suggesting new therapeutic directions in gastric cancer. Cancer Res; 76(21); 6299-310. ©2016 AACR.
authors.affiliation: Department of Bioinformatics and Computational Biology, UT MD Anderson Cancer Center, Houston, Texas.|Department of Biochemistry and Molecular Biology, Nanjing Medical University, Nanjing, P.R. China.
authors.forename: Ming
authors.initials: M
authors.lastname: Sun
authors.affiliation: Department of Oncology, Second Affiliated Hospital, Nanjing Medical University, Nanjing, P.R. China.
authors.forename: Fengqi
authors.initials: F
authors.lastname: Nie
authors.affiliation: Department of Bioinformatics and Computational Biology, UT MD Anderson Cancer Center, Houston, Texas.
authors.forename: Yunfei
authors.initials: Y
authors.lastname: Wang
authors.affiliation: Department of Pathology, First Affiliated Hospital of Nanjing Medical University, Nanjing, Jiangsu, P.R. China.
authors.forename: Zhihong
authors.initials: Z
authors.lastname: Zhang
authors.affiliation: Department of Bioinformatics and Computational Biology, UT MD Anderson Cancer Center, Houston, Texas.
authors.forename: Jiakai
authors.initials: J
authors.lastname: Hou
authors.affiliation: Department of Bioinformatics and Computational Biology, UT MD Anderson Cancer Center, Houston, Texas.
authors.forename: Dandan
authors.initials: D
authors.lastname: He
authors.affiliation: Department of Biochemistry and Molecular Biology, Nanjing Medical University, Nanjing, P.R. China.
authors.forename: Min
authors.initials: M
authors.lastname: Xie
authors.affiliation: Department of Thoracic Surgery, Nanjing Medical University Affiliated Cancer Hospital, Jiangsu Key Laboratory of Molecular and Translational Cancer Research, Cancer Institute of Jiangsu Province, Nanjing, Jiangsu, People's Republic of China.
authors.forename: Lin
authors.initials: L
authors.lastname: Xu
authors.affiliation: Department of Biochemistry and Molecular Biology, Nanjing Medical University, Nanjing, P.R. China. wangjun2016512@126.com dewei@njmu.edu.cn zhaoxiawang88@hotmail.com.
authors.forename: Wei
authors.initials: W
authors.lastname: De
authors.affiliation: Department of Oncology, Second Affiliated Hospital, Nanjing Medical University, Nanjing, P.R. China. wangjun2016512@126.com dewei@njmu.edu.cn zhaoxiawang88@hotmail.com.
authors.forename: Zhaoxia
authors.initials: Z
authors.lastname: Wang
authors.affiliation: Department of Thoracic Surgery, Peking University People' Hospital, Beijing, P.R. China. wangjun2016512@126.com dewei@njmu.edu.cn zhaoxiawang88@hotmail.com.
authors.forename: Jun
authors.initials: J
authors.lastname: Wang
mesh_terms: D000818:Animals; D017209:Apoptosis; D002465:Cell Movement; D049109:Cell Proliferation; D000076123:DNA (Cytosine-5-)-Methyltransferase 1; D004248:DNA (Cytosine-5-)-Methyltransferases / Q000502:physiology*; D050687:E2F1 Transcription Factor / Q000502:physiology; D000071221:Enhancer of Zeste Homolog 2 Protein / Q000378:metabolism; D005260:Female; D056466:Histone Demethylases / Q000502:physiology*; D006801:Humans; D051741:Kruppel-Like Transcription Factors / Q000235:genetics; D051379:Mice; D008807:Mice, Inbred BALB C; D035683:MicroRNAs / Q000502:physiology; D009361:Neoplasm Invasiveness; D063151:Polycomb Repressive Complex 2 / Q000502:physiology*; D062085:RNA, Long Noncoding / Q000502:physiology*; D012697:Serine Endopeptidases / Q000235:genetics; D013274:Stomach Neoplasms / Q000235:genetics / Q000473:pathology*; D000099271:Prostasin
chemical_list: D000076123:DNA (Cytosine-5-)-Methyltransferase 1; D004248:DNA (Cytosine-5-)-Methyltransferases; D050687:E2F1 Transcription Factor; D000071221:Enhancer of Zeste Homolog 2 Protein; D056466:Histone Demethylases; D051741:Kruppel-Like Transcription Factors; D035683:MicroRNAs; D063151:Polycomb Repressive Complex 2; D062085:RNA, Long Noncoding; D012697:Serine Endopeptidases; D000099271:Prostasin; C493753:E2F1 protein, human; C096161:KLF2 protein, human; C578622:MIRN1297 microRNA, human; C495195:KDM1A protein, human; C000619380:DNMT1 protein, human; C000619381:Dnmt1 protein, mouse; C498409:EZH2 protein, human