Downregulation of nc886 contributes to prostate cancer cell invasion and TGFβ1-induced EMT

作     者：Ronghui Yang Lingkun Zuo Hui Ma Ying Zhou Ping Zhou Liyong Wang Miao Wang Mahrukh Latif Lu Kong 

作者机构：Department of Biochemistry and Molecular BiologyCapital Medical UniversityBeijing 100069PR China Biomedical Engineering Institute of Capital Medical UniversityCapital Medical UniversityBeijing 100069PR China Department of PathologyBeijing Friendship HospitalThe Second Clinical Medical College of Capital Medical UniversityBeijing 100050PR China Department of Nuclear MedicineFourth Hospital of Hebei Medical UniversityShijiazhuangHebei 050010PR China 

出 版 物：《Genes & Diseases》 (基因与疾病（英文）)

年 卷 期：2022年第9卷第4期

页      面：1086-1098页

核心收录：

学科分类：1002[医学-临床医学] 100214[医学-肿瘤学] 10[医学] 

基　　金：This work was supported by the Scientific Research Common Program of Beijing Municipal Commission of Education (No. KM202010025004) the National Nature Science Foundation of China (No. 81672834 and 81272406) 

主　　题：EMT MET Non-coding RNA Prostate cancer TGF-β1 

摘      要：Epithelial-to-mesenchymal transition (EMT) activation is important in cancer progression and metastasis. Evidence indicates that nc886 is a representative Pol III gene that processes microRNA products via Dicer and further downregulates its target gene transforming growth factor- β1 (TGF-β1), which is the most prominent inducer of EMT in prostate cancer (PC). Consistent with the previous literature, we found that nc886 downregulation was strongly associated with metastatic behavior and showed worse outcomes in PC patients. However, little is known about the association between nc886 and the EMT signaling pathway. We developed a PC cell model with stable overexpression of nc886 and found that nc886 changed cellular morphology and drove MET. The underlying mechanism may be related to its promotion of SNAIL protein degradation via ubiquitination, but not to its neighboring genes, TGFβ-induced protein (TGFBI) and SMAD5, which are Pol II-transcribed. TGF-β1 also override nc886 promotion of MET via transient suppression the transcription of nc886, promotion of TGFBI or increase in SMAD5 phosphorylation. Both nc886 inhibition and TGFBI activation occur regardless of their methylation status. The literature suggests that MYC inhibition by TGF-β1 is attributed to nc886 downregulation. We incidentally identified MYC-associated zinc finger protein (MAZ) as a suppressive transcription factor of TGFBI, which is controlled by TGF-β1. We elucidate a new mechanism of TGF-β1 differential control of Pol II and the transcription of its neighboring Pol III gene and identify a new EMT unit consisting of nc886 and its neighboring genes.