Long non-coding RNA ZMIZ1-AS1 promotes osteosarcoma progression by stabilization of ZMIZ1.

BACKGROUND

Osteosarcomas (OS) are frequent primary sarcomas of the bone in children and adolescents. The long non-coding RNAs (lncRNAs) can affect the progression of many cancers by their sense transcripts. The present study was designed to probe the role of ZMIZ1-AS1 and the downstream pathway in OS progression.

METHODS

Cell proliferation, invasion, and migration were detected by colony formation, transwell, and wound healing assays. The binding of SOX2 or MYC protein with ZMIZ1-AS1 promoter was explored by ChIP assay and dual-luciferase reporter assay. Interaction between PTBP1 protein and ZMIZ1-AS1 (or ZMIZ1 mRNA) was detected by RIP assay.

RESULTS

SOX2 and MYC are the downstream effectors of the Hippo pathway and transcriptionally activated ZMIZ1-AS1. Compared to the controls, OS tissues and cells contained higher ZMIZ1-AS1 expression. Silencing of ZMIZ1-AS1 repressed OS cell viability, proliferation, migration, and invasion. Our findings further showed that ZMIZ1-AS1 recruits RNA-binding protein PTBP1 to stabilize ZMIZ1 mRNA. PTBP1 or ZMIZ1 overexpression rescues the suppressive effects of silenced ZMIZ1-AS1 on OS cellular processes. Importantly, ZMIZ1-AS1 promotes OS growth in vivo by stabilization of ZMIZ1.

CONCLUSIONS

Long non-coding RNA ZMIZ1-AS1 promotes OS progression by stabilization of ZMIZ1. The Hippo pathway is inactivated in osteosarcoma. Transcriptional factors SOX2 and MYC downstream the Hippo pathway induce the upregulation of ZMIZ1-AS1 in osteosarcoma. ZMIZ1-AS1 recruits RNA binding protein PTBP1 that stabilizes ZMIZ1, the sense transcript of ZMIZ1-AS1. ZMIZ1-AS1 promotes osteosarcoma cell viability, proliferation, migration, and invasion by ZMIZ1 in a PTBP1 dependent manner.