Long Noncoding RNA ANCR Attenuates The Invasion And Metastasis Of Breast Cancer

Over the past years,breast cancer has become one of the most common malignancies in women;and the distant metastasis has been reported to be the major cause of mortality in breast cancer patients.In recent years,the incidence of breast cancer has increased rapidly both in developed and in developing countries.The epithelial-mesenchymal transition(EMT),a developmental process in which epithelial cells lose their polarity and acquire the migratory properties of mesenchymal cells,is known to be a crucial mechanism contributing to cancer metastasis.Increasing evidence implicates that EMT is a pivotal step for tumor infiltration and distant metastasis in a variety of carcinomas.The long non-coding RNAs(lncRNAs)are RNA transcripts longer than 200 nucleotides with little protein-coding capacity.A great deal of emerging research works have revealed that lncRNAs are functional in multiple biological processes,including development,differentiation,cellular senescence and carcinogenesis.A multitude of evidences implie that the cancer-associated lncRNAs may have either oncogenic or tumor suppressing effects,and these lncRNAs have attracted intense research attention as a new class of potential cancer diagnostic biomarkers or therapeutic targets.One of the main molecular mechanisms of lncRNAs is that some lncRNAs can interact with proteins to influence their binding proteins stability.EZH2(the Enhancer of Zeste Homolog 2)is one component of the Polycomb Repressive Complex 2(PRC2),which catalyzes the trimethylation of Lys-27 of histone H3(H3K27me3)to suppress the transcription of target genes.EZH2 has been reported to have important parts in cancer development and metastasis progression.High expression of EZH2 has been detected in many solid tumors,including breast cancer;and EZH2 can induce and promote breast tumor EMT program.Besides,a great deal of studies have demonstrated that EZH2 can associate with a series of lncRNAs.In an initial attempt to identify lncRNAs that interact with EZH2 to regulate its stability,we have tested several lncRNAs that may potentially bind with EZH2;among these,we have focused on one lncRNA termed anti-differentiation ncRNA(ANCR),because we find it interacts with EZH2 and decreases EZH2 stability in breast cancer cells in our following research.The ANCR is an 855-nucleotide lncRNA,first reported to be downregulated during differentiation.ANCR is indispensable to enforce the undifferentiated cell state within epidermis.It has been reported that ANCR can bind with EZH2 in hFOB1.19 cells.In this study,we uncover that ANCR is associated with EZH2 to increase the bind of CDK1 with EZH2 and to promote the phosphorylation at Thr-345 and Thr-487 residues of EZH2,resulting in the ubiquitination and subsequent degradation of EZH2.Experimental data from our study also indicate that ANCR is a repressive regulator of EMT in breast cancer cells.More importantly,we demonstrate that overexpression of ANCR in malignant breast cancer cells effectively represses tumorigenesis and metastasis in vivo in immunodeficiency mice.This has been the first evidence that EZH2 stability is regulated by lncRNA,and ANCR suppresses the EMTand invasion in breast cancer cells in vitro,and that it prevents tumorigenesis and distant metastasis in animals in vivo.