The pan-cancer lncRNA PLANE regulates an alternative splicing program to promote cancer pathogenesis

Liu Teng,Yu Chen Feng,Yi Meng Yue,Li Yuan Wei,Sheng Nan Zhang,Xu Dong Zhang,Jin Ming Li,Cai Xia Tang,Pei Lin Wang,Shi Xing Wang,Xiao Ying Liu,Yujie Shi,Huixia Cao,Su Guo ,Ting La,Xiao Zhao ,Teng Qi ,Jin Gao ,Tao Liu,Rick F Thorne,Lei Jin,Fengmin Shao ,Jenny Wang ,Didi Zhang

doi:10.1038/s41467-021-24099-4

Abstract

Genomic amplification of the distal portion of chromosome 3q, which encodes a number of oncogenic proteins, is one of the most frequent chromosomal abnormalities in malignancy. Here we functionally characterise a non-protein product of the 3q region, the long noncoding RNA (lncRNA) PLANE, which is upregulated in diverse cancer types through copy number gain as well as E2F1-mediated transcriptional activation. PLANE forms an RNA-RNA duplex with the nuclear receptor co-repressor 2 (NCOR2) pre-mRNA at intron 45, binds to heterogeneous ribonucleoprotein M (hnRNPM) and facilitates the association of hnRNPM with the intron, thus leading to repression of the alternative splicing (AS) event generating NCOR2-202, a major protein-coding NCOR2 AS variant. This is, at least in part, responsible for PLANE-mediated promotion of cancer cell proliferation and tumorigenicity. These results uncover the function and regulation of PLANE and suggest that PLANE may constitute a therapeutic target in the pan-cancer context.

Highlights

Genomic amplification of the distal portion of chromosome 3q, which encodes a number of oncogenic proteins, is one of the most frequent chromosomal abnormalities in malignancy
A number of proteins encoded by genes located to the distal portion of chromosome 3q that is frequently amplified in various cancer types are known to drive cancer pathogenesis, such as the p110α subunit of phosphatidylinositol 3-kinase (PI3Kα) and eukaryotic translation initiation factor 4G48,49
We demonstrate that PLANE, a long noncoding RNA (lncRNA) encoded by a gene situated in this region, is upregulated in diverse cancer types and promotes cancer cell proliferation and tumorigenicity, uncovering a hitherto unrecognised oncogenic contribution of a non-protein-coding component of the distal portion of chromosome 3q

Summary

Introduction

Genomic amplification of the distal portion of chromosome 3q, which encodes a number of oncogenic proteins, is one of the most frequent chromosomal abnormalities in malignancy. PLANE forms an RNA-RNA duplex with the nuclear receptor co-repressor 2 (NCOR2) pre-mRNA at intron 45, binds to heterogeneous ribonucleoprotein M (hnRNPM) and facilitates the association of hnRNPM with the intron, leading to repression of the alternative splicing (AS) event generating NCOR2-202, a major protein-coding NCOR2 AS variant. This is, at least in part, responsible for PLANE-mediated promotion of cancer cell proliferation and tumorigenicity. We present evidence that the lncRNA PLANE forms an RNA–RNA duplex with the NCOR2 pre-mRNA and recruits hnRNPM, facilitating hnRNPM-mediated repression of the AS event generating NCOR2-202, a major protein-coding NCOR2 transcript variant. We show that PLANE is frequently upregulated in diverse cancer types through genomic amplification and E2F1-mediated transcriptional activation, with practical implications of interference with PLANE as potential treatment approach in the pan-cancer context

Methods

Results

Conclusion