title: The degradation of EZH2 mediated by lncRNA ANCR attenuated the invasion and metastasis of breast cancer.
abstract: EZH2 (the Enhancer of Zeste Homolog 2), as a key epigenetic regulator and EMT inducer, participates in a variety of cancer metastasis. EZH2 stability is regulated by several types of post-translational modifications (PTMs).The long non-coding RNAs (lncRNA) have been implicated to have critical roles in multiple carcinogenesis through a wide range of mechanisms, including modulating the stability of proteins. To date, whether the stability of EZH2 protein is regulated by lncRNAs remains unexplored. Here we report the discovery of ANCR modulating the stability of EZH2, and hence in the invasion and metastasis of breast cancer cells. We determined that ANCR potentiated the CDK1-EZH2 interaction, which then increased the intensity of phosphorylation at Thr-345 and Thr-487 sites of EZH2, facilitating EZH2 ubiquitination and hence its degradation. Moreover, we also uncover ANCR is an important player in breast cancer progression and metastasis mainly through decreasing EZH2 stability. More specifically, we initially found that ANCR level was lower in breast cancer tissues and breast cancer cell lines, in contrast to their normal counterparts. We then demonstrated that knockdown of ANCR induced an EMT program and promoted cell migration and invasion in MCF10A (epithelial cells), whereas ectopic expression of ANCR repressed breast cancer cells migration and invasion. Furthermore, we validated in a nude mouse model that overexpression of ANCR in highly malignant and invasive MDA-MB-231 breast cancer cells significantly reduced the ability of the cells to form tumors and prevented the lung metastasis in vivo. Based on these data, our findings define a new mechanism underlying modulation of EZH2 stability by linking ANCR interaction with EZH2 to promote its phosphorylation that facilitates EZH2 degradation and suppresses breast cancer progression.
authors.affiliation: The Key Laboratory of Molecular Epigenetics of Ministry of Education (MOE), Northeast Normal University, Changchun, China.
authors.forename: Zhongwei
authors.initials: Z
authors.lastname: Li
authors.affiliation: The Institute of Genetics and Cytology, Northeast Normal University, Changchun, China.
authors.forename: Pingfu
authors.initials: P
authors.lastname: Hou
authors.affiliation: The Key Laboratory of Molecular Epigenetics of Ministry of Education (MOE), Northeast Normal University, Changchun, China.
authors.forename: Dongmei
authors.initials: D
authors.lastname: Fan
authors.affiliation: The Key Laboratory of Molecular Epigenetics of Ministry of Education (MOE), Northeast Normal University, Changchun, China.
authors.forename: Meichen
authors.initials: M
authors.lastname: Dong
authors.affiliation: The Breast Surgery, The Tumor Hospital of Jilin Province, Changchun, China.
authors.forename: Musong
authors.initials: M
authors.lastname: Ma
authors.affiliation: The Institute of Genetics and Cytology, Northeast Normal University, Changchun, China.
authors.forename: Hongyuan
authors.initials: H
authors.lastname: Li
authors.affiliation: The Key Laboratory of Molecular Epigenetics of Ministry of Education (MOE), Northeast Normal University, Changchun, China.
authors.forename: Ruosi
authors.initials: R
authors.lastname: Yao
authors.affiliation: National Engineering Laboratory for Druggable Gene and Protein Screening, Northeast Normal University, Changchun, China.
authors.forename: Yuxin
authors.initials: Y
authors.lastname: Li
authors.affiliation: National Engineering Laboratory for Druggable Gene and Protein Screening, Northeast Normal University, Changchun, China.
authors.forename: Guannan
authors.initials: G
authors.lastname: Wang
authors.affiliation: The Institute of Genetics and Cytology, Northeast Normal University, Changchun, China.
authors.forename: Pengyu
authors.initials: P
authors.lastname: Geng
authors.affiliation: The Key Laboratory of Molecular Epigenetics of Ministry of Education (MOE), Northeast Normal University, Changchun, China.
authors.forename: Adhanom
authors.initials: A
authors.lastname: Mihretab
authors.affiliation: The Liggins Institute, The University of Auckland, Auckland, New Zealand.
authors.forename: Dongxu
authors.initials: D
authors.lastname: Liu
authors.affiliation: The Institute of Genetics and Cytology, Northeast Normal University, Changchun, China.
authors.forename: Yu
authors.initials: Y
authors.lastname: Zhang
authors.affiliation: The Key Laboratory of Molecular Epigenetics of Ministry of Education (MOE), Northeast Normal University, Changchun, China.
authors.forename: Baiqu
authors.initials: B
authors.lastname: Huang
authors.affiliation: The Institute of Genetics and Cytology, Northeast Normal University, Changchun, China.
authors.forename: Jun
authors.initials: J
authors.lastname: Lu
mesh_terms: D000818:Animals; D001943:Breast Neoplasms / Q000378:metabolism / Q000473:pathology*; D016203:CDC2 Protein Kinase / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D015820:Cadherins / Q000378:metabolism; D045744:Cell Line, Tumor; D002465:Cell Movement; D003513:Cycloheximide / Q000494:pharmacology; D000071221:Enhancer of Zeste Homolog 2 Protein / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D005260:Female; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D006801:Humans; D007976:Leupeptins / Q000494:pharmacology; D008175:Lung Neoplasms / Q000556:secondary; D061986:MCF-7 Cells; D051379:Mice; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D046988:Proteasome Endopeptidase Complex / Q000737:chemistry / Q000378:metabolism; D011485:Protein Binding; D062085:RNA, Long Noncoding / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D025801:Ubiquitin / Q000378:metabolism
chemical_list: C571057:ANCR long noncoding RNA, human; D015820:Cadherins; D007976:Leupeptins; D062085:RNA, Long Noncoding; D025801:Ubiquitin; D003513:Cycloheximide; C498409:EZH2 protein, human; D000071221:Enhancer of Zeste Homolog 2 Protein; D016203:CDC2 Protein Kinase; C528899:CDK1 protein, human; D046988:Proteasome Endopeptidase Complex; C072553:benzyloxycarbonylleucyl-leucyl-leucine aldehyde