LncRNA CANT1 suppresses retinoblastoma progression by repellinghistone methyltransferase in PI3K\u03b3 promoter

Jiayan Fan,Xianqun Fan,Shengfang Ge,Shaoyun Wang,Hongyan Ni,Yue Xing,Yefei Wang,Jie Yu,Renbing Jia,Peiwei Chai

doi:10.1038/s41419-020-2524-y

Abstract

Retinoblastoma (RB) is the most common malignant intraocular tumor of childhood. Recent studies have shown that long noncoding RNAs (lncRNAs), which are longer than 200 bp and without protein-coding ability, are key regulators of tumorigenesis. However, the role of lncRNAs in retinoblastoma remains to be elucidated. In this study, we found that the expression of lncRNA CASC15-New-Transcript 1 (CANT1) was significantly downregulated in RB. Notably, overexpression of CANT1 significantly inhibited RB growth both in vitro and in vivo. Furthermore, lncRNA CANT1, which was mainly located in the nucleus, occupied the promoter of phosphoinositide 3-kinase gamma (PI3Kγ) and blocked histone methyltransferase hSET1 from binding to the PI3Kγ promoter, thus abolishing hSET1-mediated histone H3K4 trimethylation of the PI3Kγ promoter and inhibiting PI3Kγ expression. Furthermore, we found that silencing PI3Kγ either by lncRNA CANT1 overexpression or by PI3Kγ siRNA, reduced the activity of PI3K/Akt signaling and suppressed RB tumorigenesis. In summary, lncRNA CANT1 acts as a suppressor of RB progression by blocking gene-specific histone methyltransferase recruitment. These findings outline a new CANT1 modulation mechanism and provide an alternative option for the RB treatment.

Highlights

Introduction Long noncodingRNAs are transcripts longer than 200 bp with no apparent protein-coding ability, that are involved in numerous important biological phenomena such as X chromosome inactivation, chromosome conformation shaping, and DNA damage repair[1,2,3,4]
Different transcripts exist on the chromosome 6p22.3 locus in different tissues, for example, CASC15 is 1902 bp in length with 12 exons according to databases in the University of California, Santa Cruz (UCSC) and National Center for Biotechnology Information (NCBI) databases, and long noncoding RNAs (lncRNAs) CASC15-New-Transcript 1 (CANT1) (GenBank: KP981381.1) is 1114 bp with 7 exons, which was confirmed by our previous research[15]
We revealed that a novel inactivated lncRNA, CANT1, at chromosome 6p22.3 modulates RB tumorigenesis through the epigenetic activation of PI3Kγ expression, enhancing PI3K/Akt signaling and accelerating tumor progression (Fig. 7e)

Summary

Introduction

RNAs (lncRNAs) are transcripts longer than 200 bp with no apparent protein-coding ability, that are involved in numerous important biological phenomena such as X chromosome inactivation, chromosome conformation shaping, and DNA damage repair[1,2,3,4]. The functional roles and mechanism of action of some classically defined lncRNAs are well understood. LncRNA XIST coats the X chromosome, is expressed only from the inactive X chromosome (Xi), and is essential for the silencing process[2,5,6]. As lncRNAs play a key role in the maintenance of homeostasis, aberrant lncRNA expression may be an important trigger for a variety of diseases.

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Conclusion