Long noncoding RNA TTN-AS1 facilitates tumorigenesis and metastasis by maintaining TTN expression in skin cutaneous melanoma

Ying Wang,Jiqiang Lu,Dongping Li,Shengnan Zhang,Weiyan Qi,Hanmei Xu,Lin Chen,Weiguang Li

doi:10.1038/s41419-020-02895-y

Ying Wang, Jiqiang Lu + Show 6 more

Open Access

https://doi.org/10.1038/s41419-020-02895-y

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Journal: Cell Death & Disease	Publication Date: Aug 1, 2020
Citations: 27	License type: open-access

Affiliation: China Pharmaceutical University

Abstract

The antisense transcript, emanating from the opposite strand to a protein-coding or sense strand, has been reported to have critical roles in gene regulation. The perturbation of an antisense RNA can alter the expression of sense messenger RNAs. In this study, a long noncoding RNA TTN-AS1 (lncRNA-TTN-AS1), which is transcribed in the opposite direction of the human titin (TTN) gene, has been identified and explored in skin cutaneous melanoma (SKCM). We found that the expression of TTN and lncRNA-TTN-AS1 had a significantly positive correlation in SKCM cells. Functionally, ectopic expression of TTN and lncRNA-TTN-AS1 promoted SKCM tumorigenesis and metastasis both in vitro and in vivo. Moreover, knockdown of TTN partially abrogated lncRNA-TTN-AS1 induced SKCM tumorigenesis. Mechanistically, hypomethylation of transcription initiation site was responsible for lncRNA-TTN-AS1 high expression levels. LncRNA-TTN-AS1 facilitated SKCM progression by promoting TTN expression at both transcriptional and posttranscriptional levels. As detailed, lncRNA-TTN-AS1 had a significant effect on the increase of TTN promoter activity. Besides, lncRNA-TTN-AS1 also induced the accumulation of TTN in cytoplasm by increasing the stability of TTN mRNA. Clinically, we found that high TTN and lncRNA-TTN-AS1 expression were positively correlated with poor overall survival of SKCM patients, and may be considered as novel biomarkers and drug targets for SKCM patients.

Highlights

Skin cutaneous melanoma (SKCM) is the most malignant tumor type in skin cancers and the 5-year overall survival (OS) rate of SKCM patients is still unsatisfactory[1]
We found that Long noncoding RNAs (lncRNAs)-TTN-AS1 upregulates actinbinding protein fascin homolog 1 (FSCN1) by sponging miR-133b, and combines directly with the mRNAstabilizing protein HuR to stabilize FSCN1 mRNA, resulting in the epithelial-mesenchymal transition cascade in esophageal squamous cell carcinoma (ESCC)[8]
Survival curves calculated by Kaplan–Meier and log-rank tests revealed that SKCM patients with higher TTN and lncRNA-TTN-AS1 expression had shorter OS than those with lower TTN and lncRNA-TTN-AS1 expression (Fig. 1a, b)

Summary

Introduction

Skin cutaneous melanoma (SKCM) is the most malignant tumor type in skin cancers and the 5-year overall survival (OS) rate of SKCM patients is still unsatisfactory[1]. Long noncoding RNAs (lncRNAs), a class of noncoding RNAs, has been reported to have abundant functions in development of cancers[3,4], among which the antisense transcript was once considered to be transcriptional noise. The antisense transcript, emanating from the opposite strand to a protein-coding or sense strand, were recently shown to play a vital role in gene regulation of the corresponding sense transcripts[5,6]. ANRIL is transcribed from the opposite direction of INK4A-ARFINK4B gene cluster and may exert its oncogenic action in melanoma by suppressing the expression of INK4A and INK4B7. We reported an antisense transcript lncRNA-TTN-AS1 (ENST00000589434), which is transcribed in the opposite direction of the human titin (TTN)

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