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

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

doi:10.3389/fonc.2021.592045

Abstract

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

Highlights

Hepatocellular carcinoma (HCC) is one of the most common cancers and the third leading cause of cancer-related deaths worldwide [1]
Noncoding transcript in T cells (NTT) was most significantly downregulated in hepatocellular carcinoma (HCC), while a higher NTT level correlated with a shorter survival time of patients with HCC
chromatin immunoprecipitation (ChIP) of HCC cell lines revealed that NTT is regulated by the transcription factor ATF3 and binds to the MYB promoter via the activated complex

Summary

Introduction

Hepatocellular carcinoma (HCC) is one of the most common cancers and the third leading cause of cancer-related deaths worldwide [1]. HCC accounts for more than 90% of liver cancers [2]. The risk factors for developing HCC include infection with hepatitis B or C virus, alcohol abuse, nonalcoholic fatty liver disease, Budd–Chiari syndrome, aflatoxin B1 intake, and metabolic diseases [3, 4]. The sensitivity and specificity of AFP for the diagnosis of HCC (cutoff 20 ng/ml) are 53% and 90%, respectively. AFP has been removed from the HCC surveillance guidelines of the American Association for the Study of Liver Disease due to its low diagnostic accuracy [2, 6, 7]. Cell-free nucleic acids could contribute to the surveillance and diagnosis of HCC [8]. This study examined the role of lncRNA NTT in the development and progression of cancer

Methods

Results

Conclusion