LncRNA GOLGA2P10 is induced by PERK/ATF4/CHOP signaling and protects tumor cells from ER stress-induced apoptosis by regulating Bcl-2 family members

Meng-Zhi Wu,Jin-E Yang,Jin-Xi Chen,Ying-Ying Lin,Tao Fu,Shi-Mei Zhuang

doi:10.1038/s41419-020-2469-1

Abstract

Elevated endoplasmic reticulum (ER) stress is frequently observed in cancers, whereas sustained ER stress may trigger apoptosis. How cancer cells escape from ER stress-induced apoptosis remain unclear. Here, we found that a pseudogene-derived lncRNA, Golgin A2 pseudogene 10 (GOLGA2P10), was frequently upregulated in HCC tissues and significantly elevated in hepatoma cells treated with ER stress inducers, such as tunicamycin and thapsigargin. Higher GOLGA2P10 level was correlated with shorter recurrence-free survival of HCC patients. Upon ER stress, CHOP directly bound to the promoter of GOLGA2P10 and induced its transcription via the PERK/ATF4/CHOP pathway. Interestingly, the ER stress inducer-stimulated apoptosis was promoted by silencing GOLGA2P10 but was antagonized by overexpressing GOLGA2P10. Both gain- and loss-of-function analyses disclosed that GOLGA2P10 increased BCL-xL protein level, promoted BAD phosphorylation, and conferred tumor cells with resistance to ER stress-induced apoptosis. Moreover, BCL-xL overexpression or BAD knockdown abrogated the apoptosis-promoting effect of GOLGA2P10 silencing. Consistently, the Ser75Ala mutation in BAD, which caused phosphorylation-resistance, further enhanced the promoting effect of BAD in tunicamycin-induced apoptosis. These results suggest that ER stress induces GOLGA2P10 transcription through the PERK/ATF4/CHOP pathway, and upregulation of GOLGA2P10 protects tumor cells from the cytotoxic effect of persistent ER stress in tumor microenvironment by regulating Bcl-2 family members, which highlight GOLGA2P10 as a potential target for anticancer therapy.

Highlights

Introduction Long noncodingRNAs belong to a class of non-protein coding transcripts that are longer than 200 nucleotides 1
To test whether these Long noncodingRNAs (lncRNAs) were upregulated by endoplasmic reticulum (ER) stress, three hepatoma cell lines, including MHCC-97H, QGY-7703, and SKHEP-1, were treated with ER stress inducer tunicamycin or thapsigargin
GOLGA2P10 level (Supplementary Fig. 2a, b). These findings suggest that GOLGA2P10 may be upregulated upon ER stress

Summary

Introduction

Introduction Long noncodingRNAs (lncRNAs) belong to a class of non-protein coding transcripts that are longer than 200 nucleotides 1. A number of lncRNAs have been shown to play vital roles in different physiological and pathological processes, including tumor development[2,3,4]. ER stress has been implicated in various pathological processes, like neurodegenerative diseases, diabetes, metabolic syndromes, and tumor development[12,13,14,15]. Further investigation revealed that CHOP directly bound to the GOLGA2P10 promoter and induced its transcription via the PERK/ATF4/CHOP pathway. Both gain- and loss-of-function analyses revealed that GOLGA2P10 conferred tumor cells with resistance to ER stress-induced apoptosis by increasing the protein level of BCL-xL and promoting phosphorylation of BAD. Our data disclose the novel biological function of a lncRNA in ER stress-induced apoptosis, and highlight GOLGA2P10 as a potential target for anticancer therapy

Methods

Results

Conclusion