miR-23b/SP1/c-myc forms a feed-forward loop supporting multiple myeloma cell growth

• Published in: Blood cancer journal (New York) Vol. 6; no. 1; p. e380
• Main Authors: Fulciniti, M, Amodio, N, Bandi, R L, Cagnetta, A, Samur, M K, Acharya, C, Prabhala, R, D'Aquila, P, Bellizzi, D, Passarino, G, Adamia, S, Neri, A, Hunter, Z R, Treon, S P, Anderson, K C, Tassone, P, Munshi, N C
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 01.01.2016; Springer Nature B.V; Nature Publishing Group
• Subjects: 631/67/1990/804; 692/308/2778; Animals; Base Sequence; Binding Sites; Biomedical and Life Sciences; Biomedicine; Cancer Research; Caspase 3 - metabolism; Cell Line, Tumor; Cell Proliferation; Cell Survival - genetics; Disease Models, Animal; DNA Methylation; Down-Regulation; Gene Expression; Gene Expression Profiling; Gene Expression Regulation, Neoplastic; Gene Regulatory Networks; Gene Silencing; Genes, Reporter; Hematology; Humans; MicroRNAs - chemistry; MicroRNAs - genetics; Multiple Myeloma - genetics; Multiple Myeloma - metabolism; Multiple Myeloma - pathology; Oncology; Original; original-article; Promoter Regions, Genetic; Proto-Oncogene Proteins c-myc - chemistry; Proto-Oncogene Proteins c-myc - genetics; Proto-Oncogene Proteins c-myc - metabolism; RNA Interference; RNA, Messenger - chemistry; RNA, Messenger - genetics; Sp1 Transcription Factor - chemistry; Sp1 Transcription Factor - genetics; Sp1 Transcription Factor - metabolism
• ISSN: 2044-5385; 2044-5385
• DOI: 10.1038/bcj.2015.106

Deregulated microRNA (miR)/transcription factor (TF)-based networks represent a hallmark of cancer. We report here a novel c-Myc/miR-23b/Sp1 feed-forward loop with a critical role in multiple myeloma (MM) and Waldenstrom’s macroglobulinemia (WM) cell growth and survival. We have found miR-23b to be downregulated in MM and WM cells especially in the presence of components of the tumor bone marrow milieu. Promoter methylation is one mechanism of miR-23b suppression in myeloma. In gain-of-function studies using miR-23b mimics-transfected or in miR-23b-stably expressing MM and WM cell lines, we observed a significant decrease in cell proliferation and survival, along with induction of caspase-3/7 activity over time, thus supporting a tumor suppressor role for miR-23b. At the molecular level, miR-23b targeted Sp1 3′UTR and significantly reduced Sp1-driven nuclear factor-κB activity. Finally, c-Myc, an important oncogenic transcription factor known to stimulate MM cell proliferation, transcriptionally repressed miR-23b. Thus MYC -dependent miR-23b repression in myeloma cells may promote activation of oncogenic Sp1-mediated signaling, representing the first feed-forward loop with critical growth and survival role in myeloma.