MYC Targeted Long Noncoding RNA DANCR Promotes Cancer in Part by Reducing p21 Levels

• Published in: Cancer research (Chicago, Ill.) Ill.), 2018-01, Vol.78 (1), p.64-74
• Main Authors: Lu, Yunqi, Hu, Zhongyi, Mangala, Lingegowda S, Stine, Zachary E, Hu, Xiaowen, Jiang, Dahai, Xiang, Yan, Zhang, Youyou, Pradeep, Sunila, Rodriguez-Aguayo, Cristian, Lopez-Berestein, Gabriel, DeMarzo, Angelo M, Sood, Anil K, Zhang, Lin, Dang, Chi V
• Format: Article
• Language: English
• Subjects: Animals; Cell growth; Cell Line, Tumor; Cell proliferation; Cyclin-dependent kinase inhibitor p21; Cyclin-Dependent Kinase Inhibitor p21 - genetics; Cyclin-Dependent Kinase Inhibitor p21 - metabolism; Female; Gene expression; Gene Expression Regulation, Neoplastic; Genes, myc; Humans; Lymphoma; Lymphoma, B-Cell - genetics; Lymphoma, B-Cell - pathology; Male; Mice, Nude; Myc protein; Nanoparticles; Ovarian cancer; Ovarian carcinoma; Ovarian Neoplasms - genetics; Ovarian Neoplasms - pathology; Prostate; Prostatic Neoplasms - genetics; Prostatic Neoplasms - pathology; RNA, Long Noncoding - genetics; siRNA; Transcription; Tumor cell lines; Xenograft Model Antitumor Assays; Xenografts
• ISSN: 0008-5472; 1538-7445
• DOI: 10.1158/0008-5472.can-17-0815

The MYC oncogene broadly promotes transcription mediated by all nuclear RNA polymerases, thereby acting as a positive modifier of global gene expression. Here, we report that MYC stimulates the transcription of DANCR, a long noncoding RNA (lncRNA) that is widely overexpressed in human cancer. We identified DANCR through its overexpression in a transgenic model of MYC-induced lymphoma, but found that it was broadly upregulated in many human cancer cell lines and cancers, including most notably in prostate and ovarian cancers. Mechanistic investigations indicated that DANCR limited the expression of cell-cycle inhibitor p21 (CDKN1A) and that the inhibitory effects of DANCR loss on cell proliferation could be partially rescued by p21 silencing. In a xenograft model of human ovarian cancer, a nanoparticle-mediated siRNA strategy to target DANCR was sufficient to strongly inhibit tumor growth. Our observations expand knowledge of how MYC drives cancer cell proliferation by identifying DANCR as a critical lncRNA widely overexpressed in human cancers. These findings expand knowledge of how MYC drives cancer cell proliferation by identifying an oncogenic long noncoding RNA that is widely overexpressed in human cancers. .