LncRNA RP11-295G20.2 regulates hepatocellular carcinoma cell growth and autophagy by targeting PTEN to lysosomal degradation

Shenglin Huang,Lin Huan,Linhui Liang,Yangjun Wu,Jiajia Wang,Xianghuo He

doi:10.1038/s41421-021-00339-1

Abstract

PTEN is a crucial tumor suppressor and loss of PTEN protein is involved in various cancers. However, the detailed molecular mechanisms of PTEN loss in cancers remain elusive, especially the involvement of lncRNAs. Here, lncRNA RP11-295G20.2 is found to be significantly upregulated in hepatocellular carcinoma (HCC) and promotes the growth of liver cancer cells both in vitro and in vivo. Furthermore, RP11-295G20.2 inhibits autophagy in liver cancer cells. Interestingly, RP11-295G20.2 directly binds to the PTEN protein and leads to its degradation. RP11-295G20.2 expression is inversely correlated with PTEN protein expression in 82 TCGA/TCPA-LIHC samples. Surprisingly, RP11-295G20.2-induced PTEN degradation occurs through the lysosomal pathway instead of the proteasome pathway. RP11-295G20.2 binds to the N terminus of PTEN and facilitates the interaction of p62 with PTEN. Thus, PTEN is translocated into lysosomes and degraded. RP11-295G20.2 also influences AKT phosphorylation and forkhead box O 3a (FOXO3a) translocation into the nucleus, in turn regulating the transcription of autophagy-related genes. Collectively, RP11-295G20.2 directly binds to PTEN and enables its lysosomal degradation. This newly identified RP11-295G20.2/PTEN axis reveals an unexplored molecular mechanism regarding PTEN loss in liver cancer and might provide new therapeutic benefits for liver cancer patients.

Highlights

Over the last decades, reports have indicated that the human genome is pervasively transcribed[1]
To investigate the role of long noncoding RNAs (lncRNAs) in hepatocellular carcinoma (HCC), we analyzed the expression of lncRNAs in 50 pairs of HCC samples[9] and selected several high-abundance lncRNAs (Fig. 1a)
We analyzed the differentially expressed lncRNAs in HCC samples and found that RP11-295G20.2 was significantly upregulated in HCC samples

Summary

Introduction

Reports have indicated that the human genome is pervasively transcribed[1]. Protein-coding genes compose less than 2% of the human genome, and the remaining transcripts have no or little protein-coding potential[1]. Among these noncoding transcripts, one class of noncoding RNAs named long noncoding RNAs (lncRNAs) is emerging as an attractive hotspot in cancer research. LncRNAs contain more than 200 nucleotides and have no protein-coding potential[2]. LncRNAs show tissue-specific and diseasespecific expression patterns[3], which suggests that they hold strong promise for the diagnosis and treatment of cancers.

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Conclusion