title: The role of c-Myc-RBM38 loop in the growth suppression in breast cancer.
abstract: RNA-binding protein 38 (RBM38) is a member of the RNA recognition motif (RRM) family of RNA-binding proteins (RBPs). RBM38 often exerts its function by forming regulatory loops with relevant genes. c-Myc is an oncogenic transcription factor that is upregulated in one-third of breast cancers and involved in many cellular processes in this malignancy. In our previous study, RBM38 was identified as a tumor suppressor in breast cancer. In the present study, we investigated the mechanisms underlying the regulation of this tumor suppressor.
  
  
  
  Lentivirus transfections, Western blotting analysis, qRT-PCR and immunohistochemistry were employed to study the expression of c-Myc and RBM38. Chromatin immunoprecipitation and dual-luciferase reporter assays were performed to investigate the direct relationship between c-Myc protein and the RBM38 gene. RNA immunoprecipitation combined with dual-luciferase reporter assays was conducted to confirm the direct relationship between the RBM38 protein and the c-Myc transcript.
  
  
  
  Knockdown of c-Myc increased RBM38 expression by binding directly to specific DNA sequences (5'-CACGTG-3'), known as the E-box motif, in the promoter region of RBM38 gene. Additionally, RBM38 destabilized the c-Myc transcript by directly targeting AU-rich elements (AREs) in the 3'-untranslated region (3'-UTR) of c-Myc mRNA to suppress c-Myc expression. Moreover, specific inhibitors of c-Myc transcriptional activity inhibited RBM38-induced suppression of growth, implying that RBM38 acts as a tumor suppressor via a mechanism that depends, at least partially, on the reduction of c-Myc expression in breast cancer.
  
  
  
  RBM38 and c-Myc form a unique mutually antagonistic RBM38-c-Myc loop in breast cancer.
authors.affiliation: Jiangsu Breast Disease Center, the First Affiliated Hospital with Nanjing Medical University, 300 Guangzhou Road, Nanjing, 210029, China.
authors.forename: Xiao-Xia
authors.initials: XX
authors.lastname: Li
authors.affiliation: Jiangsu Breast Disease Center, the First Affiliated Hospital with Nanjing Medical University, 300 Guangzhou Road, Nanjing, 210029, China.
authors.forename: Liang
authors.initials: L
authors.lastname: Shi
authors.affiliation: Jiangsu Breast Disease Center, the First Affiliated Hospital with Nanjing Medical University, 300 Guangzhou Road, Nanjing, 210029, China.
authors.forename: Xu-Jie
authors.initials: XJ
authors.lastname: Zhou
authors.affiliation: Jiangsu Breast Disease Center, the First Affiliated Hospital with Nanjing Medical University, 300 Guangzhou Road, Nanjing, 210029, China.
authors.forename: Jing
authors.initials: J
authors.lastname: Wu
authors.affiliation: Jiangsu Breast Disease Center, the First Affiliated Hospital with Nanjing Medical University, 300 Guangzhou Road, Nanjing, 210029, China.
authors.forename: Tian-Song
authors.initials: TS
authors.lastname: Xia
authors.affiliation: Jiangsu Breast Disease Center, the First Affiliated Hospital with Nanjing Medical University, 300 Guangzhou Road, Nanjing, 210029, China.
authors.forename: Wen-Bin
authors.initials: WB
authors.lastname: Zhou
authors.affiliation: Jiangsu Breast Disease Center, the First Affiliated Hospital with Nanjing Medical University, 300 Guangzhou Road, Nanjing, 210029, China.
authors.forename: Xi
authors.initials: X
authors.lastname: Sun
authors.affiliation: Jiangsu Breast Disease Center, the First Affiliated Hospital with Nanjing Medical University, 300 Guangzhou Road, Nanjing, 210029, China.
authors.forename: Lei
authors.initials: L
authors.lastname: Zhu
authors.affiliation: Research Division of Clinical Pharmacology, the First Affiliated Hospital with Nanjing Medical University, 300 Guangzhou Road, Nanjing, 210029, China. weijifu@hotmail.com.
authors.forename: Ji-Fu
authors.initials: JF
authors.lastname: Wei
authors.affiliation: Jiangsu Breast Disease Center, the First Affiliated Hospital with Nanjing Medical University, 300 Guangzhou Road, Nanjing, 210029, China. dingqiang@njmu.edu.cn.
authors.forename: Qiang
authors.initials: Q
authors.lastname: Ding
mesh_terms: D020413:3' Untranslated Regions; D001943:Breast Neoplasms / Q000235:genetics / Q000378:metabolism*; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D061986:MCF-7 Cells; D009367:Neoplasm Staging; D011401:Promoter Regions, Genetic; D016271:Proto-Oncogene Proteins c-myc / Q000235:genetics* / Q000378:metabolism*; D016601:RNA-Binding Proteins / Q000235:genetics* / Q000378:metabolism*
chemical_list: D020413:3' Untranslated Regions; C489427:MYC protein, human; D016271:Proto-Oncogene Proteins c-myc; C515435:RBM38 protein, human; D016601:RNA-Binding Proteins
keywords: Breast cancer; Growth suppression; RBM38; c-Myc; mRNA stability