AUTHOR=Chang Ya-Sian , Lee Ya-Ting , Yen Ju-Chen , Chang Yuli C. , Lin Li-Li , Chan Wen-Ling , Chang Wei-Chiao , Lin Shyr-Yi , Chang Jan-Gowth 

TITLE=Long Noncoding RNA NTT Context-Dependently Regulates MYB by Interacting With Activated Complex in Hepatocellular Carcinoma Cells

JOURNAL=Frontiers in Oncology

VOLUME=11

YEAR=2021

URL=https://www.frontiersin.org/journals/oncology/articles/10.3389/fonc.2021.592045

DOI=10.3389/fonc.2021.592045

ISSN=2234-943X

ABSTRACT=<sec><title>Background</title><p>Long noncoding RNA (lncRNA) mediates the pathogenesis of various diseases, including cancer and cardiovascular, infectious, and metabolic diseases. This study examined the role of lncRNA <italic>NTT</italic> in the development and progression of cancer.</p></sec><sec><title>Methods</title><p>The expression of <italic>NTT</italic> was determined using tissues containing complementary DNA (cDNA) from patients with liver, lung, kidney, oral, and colon cancers. The expression of <italic>cis-</italic>acting genes adjacent to the <italic>NTT</italic> locus (<italic>CTGF</italic>, <italic>STX7</italic>, <italic>MYB</italic>, <italic>BCLAF1</italic>, <italic>IFNGR1</italic>, <italic>TNFAIP3</italic>, and <italic>HIVEP2</italic>) was also assessed. We used knockdown and chromatin immunoprecipitation (ChIP) assays to identify the <italic>cis-</italic>acting genes that interact with <italic>NTT</italic>.</p></sec><sec><title>Results</title><p><italic>NTT</italic> was most significantly downregulated in hepatocellular carcinoma (HCC), while a higher <italic>NTT</italic> level correlated with a shorter survival time of patients with HCC. Multivariate analysis indicated <italic>NTT</italic> was not an independent predictor for overall survival. <italic>MYB</italic> was significantly upregulated, and its increased expression was associated with dismal survival in HCC patients, similar to the results for <italic>NTT</italic>. <italic>NTT</italic> knockdown significantly decreased cellular migration. ChIP of HCC cell lines revealed that <italic>NTT</italic> is regulated by the transcription factor ATF3 and binds to the <italic>MYB</italic> promoter <italic>via</italic> the activated complex. Additionally, when <italic>NTT</italic> was knocked down, the expression of <italic>MYB</italic> target genes such as <italic>Bcl-xL</italic>, <italic>cyclinD1</italic>, and <italic>VEGF</italic> was also downregulated. <italic>NTT</italic> could play a positive or negative regulator for <italic>MYB</italic> with a context-dependent manner in both HCC tissues and animal model.</p></sec><sec><title>Conclusion</title><p>Our study suggests that <italic>NTT</italic> plays a key role in HCC progression <italic>via MYB</italic>-regulated target genes and may serve as a novel therapeutic target.</p></sec>