Abstract
Adrenocortical carcinoma is one of the aggressive malignancies and it originates from the cortex of adrenal gland. Dysregulation of long non-coding RNA plays important roles in the development of adrenocortical carcinoma. Here, we found that lncRNA ASB16-AS1 was down-regulated in adrenocortical carcinoma and ASB16-AS1 functions as tumor suppressor in vitro and in vivo. We then found that IGF1R and CDK6 are regulated by ASB16-AS1 in adrenocortical carcinoma cells by transcriptome RNA sequencing. ASB16-AS1 associates with RNA-binding protein HuR (ELAVL1) as revealed by RNA pull-down following mass spectrometry. Also, ASB16-AS1 inhibits HuR expression post-translationally by promoting its ubiquitination. ASB16-AS1 regulates IGF1R and CDK6 mRNA expression through RNA-binding protein HuR. We then found that inhibition of ASB16-AS1 attenuates the binding of ubiquitin E3 ligase BTRC to HuR and subsequently inhibits HuR protein unbiquitination and degradation. BTRC knock-down could reverse the effect of AB16-AS1 on HuR, CDK6, and IGF1R levels. Collectively, these results demonstrate that ASB16-AS1 regulates adrenocortical carcinoma cell proliferation and tackling the level of ASB16-AS1 may be developed to treat adrenocortical carcinoma.
Highlights
Adrenocortical carcinoma is a rare and aggressive malignancy that comes from the cortex of adrenal gland
To investigate whether ASB16-AS1 participates in the pathogenesis of adrenocortical carcinoma, we analyzed the expression of ASB16-AS1 in adrenocortical carcinoma using gene expression profiling interactive analysis (GEPIA) tool whose data were obtained from TCGA and GTEx
We validated the RNA-sequencing results by Quantitative real-time PCR (qRT-PCR) and the results demonstrate that IGF1R and CDK6 mRNA levels were increased upon knockdown of ASB16-AS1 (Fig. 4c, d)
Summary
Adrenocortical carcinoma is a rare and aggressive malignancy that comes from the cortex of adrenal gland. This type of malignancy lacks effective treatment and mostly results in poor outcomes[1]. LncRNAs exert their function in cis regulating nearby gene expression or leaving the site of transcription and perform cellular function in trans[5,6,7]. Recent studies have found that lncRNAs mediate cancer signaling pathways by interaction with proteins. These proteins underwent posttranslational modifications and the abundance of proteins are modulated by lncRNAs8,9. Human antigen R (HuR) is the ubiquitous member of embryonic lethal abnormal vision (ELAV) family of RNA-binding proteins. HuR binds transcripts in the AU-rich element and promotes
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