Antisense RNAs Influence Promoter Usage of Their Counterpart Sense Genes in Cancer

Multiple noncoding natural antisense transcripts (ncNAT) are known to modulate key biological events such as cell growth or differentiation. However, the actual impact of ncNATs on cancer progression remains largely unknown. In this study, we identified a complete list of differentially expressed nc...

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Published in:Cancer research (Chicago, Ill.) Ill.), 2021-12, Vol.81 (23), p.5849-5861
Main Authors: Bellido Molias, Fernando, Sim, Andre, Leong, Ka Wai, An, Omer, Song, Yangyang, Ng, Vanessa Hui En, Lim, Max Wei Jie, Ying, Chen, Teo, Jasmin Xin Jia, Göke, Jonathan, Chen, Leilei
Format: Article
Language:English
Subjects:
Animals
Biomarkers, Tumor - genetics
Biomarkers, Tumor - metabolism
Carcinoma, Hepatocellular - genetics
Carcinoma, Hepatocellular - metabolism
Carcinoma, Hepatocellular - pathology
Choline Kinase - antagonists & inhibitors
Choline Kinase - genetics
Choline Kinase - metabolism
Gene Expression Regulation, Neoplastic
Genome and Epigenome
Hepatocyte Nuclear Factor 4 - antagonists & inhibitors
Hepatocyte Nuclear Factor 4 - genetics
Hepatocyte Nuclear Factor 4 - metabolism
Humans
Liver Neoplasms - genetics
Liver Neoplasms - metabolism
Liver Neoplasms - pathology
Male
Membrane Proteins - antagonists & inhibitors
Membrane Proteins - genetics
Membrane Proteins - metabolism
Mice
Mice, SCID
Prognosis
Promoter Regions, Genetic
RNA, Antisense - genetics
Sphingosine N-Acyltransferase - antagonists & inhibitors
Sphingosine N-Acyltransferase - genetics
Sphingosine N-Acyltransferase - metabolism
Tumor Cells, Cultured
Tumor Suppressor Proteins - antagonists & inhibitors
Tumor Suppressor Proteins - genetics
Tumor Suppressor Proteins - metabolism
Xenograft Model Antitumor Assays
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Summary:Multiple noncoding natural antisense transcripts (ncNAT) are known to modulate key biological events such as cell growth or differentiation. However, the actual impact of ncNATs on cancer progression remains largely unknown. In this study, we identified a complete list of differentially expressed ncNATs in hepatocellular carcinoma. Among them, a previously undescribed ncNAT suppressed cancer cell growth by regulating its sense gene , a well-known cancer driver, through a promoter-specific mechanism. selectively activated the P1 promoter via HNF1A, which upregulated expression of tumor suppressor P1-driven isoforms, while having no effect on the oncogenic P2 promoter. RNA-seq data from 23 tissue and cancer types identified approximately 100 ncNATs whose expression correlated specifically with the activity of one promoter of their associated sense gene. Silencing of two of these ncNATs and (antisense to and , respectively) altered the promoter usage of and . Altogether, these results demonstrate that promoter-specific regulation is a mechanism used by ncNATs for context-specific control of alternative isoform expression of their counterpart sense genes. SIGNIFICANCE: This study characterizes a previously unexplored role of ncNATs in regulation of isoform expression of associated sense genes, highlighting a mechanism of alternative promoter usage in cancer.
ISSN:0008-5472
1538-7445
DOI:10.1158/0008-5472.CAN-21-1859