SHQ1 is an ER stress response gene that facilitates chemotherapeutics-induced apoptosis via sensitizing ER-stress response

Huimin Liu,Siqi Xie,Fang Fang,Weihua Xiao,Dhananjaya V. Kalvakolanu

doi:10.1038/s41419-020-2656-0

Abstract

SHQ1 was reported to control the biogenesis and assembly of H/ACA ribonucleoprotein particles (RNPs). It was independently isolated as a growth suppressor, GRIM1, in a genetic screen. Recent studies have indicated that SHQ1 inhibits prostate cancer growth and metastasis. SHQ1 facilitates MYC RNA splicing to promote T-acute lymphoblastic leukemia (T-ALL) development. Thus, the mechanisms of SHQ1 in cancers remain largely unknown. We report here that SHQ1 promotes tumor apoptosis and chemo-sensitivity in hepatocellular carcinoma (HCC) cells. In HCC tissues from patients, expression of SHQ1 was significantly decreased in the tumor compared to adjacent tissues. Experiments with HCC xenograft models revealed that restoring SHQ1 levels enhanced the anti-tumor activity of the endoplasmic reticulum (ER) stress inducer tunicamycin (TM) and common chemotherapy drug paclitaxel (PTX). Mechanistically, SHQ1 is an ER-stress response gene which is regulated by p50ATF6 and XBP1s through an ER stress response like element located on the SHQ1 promoter. SHQ1 interacts with the ER chaperone GRP78 to release ER sensors PERK/IRE1α/ATF6 from GRP78/ER-sensor complexes, leading to hyper-activation of unfolded protein response (UPR). In the persistent ER stress conditions of a HepG2 xenograft tumor model, SHQ1-mediated hyper-activation of ER-sensor signaling induces apoptosis. Our study thus demonstrates a SHQ1-mediated ER-stress response feedback loop that promotes tumor sensitivity to chemotherapeutics.

Highlights

Introduction Given the evidence thatSHQ1, named GRIM1, is isolated as a growth suppressor using genetic approaches[1]
SHQ1 is an endoplasmic reticulum (ER) stress response gene Previous studies have associated the lack of the chromosome 3p SHQ1 locus with both prostate and cervical carcinoma[4,5], and SHQ1 expression is dramatically reduced in human primary prostate tumors[3], findings suggesting that SHQ1 may limit the formation of such tumors
Some studies have indicated that unfolded protein response (UPR) activated by ER stress is involved in the initiation and progression of HCC13, and UPR signaling promotes a malignant phenotype and helps tumors become more resistant to chemotherapy in breast cancer[24]

Summary

Introduction

SHQ1, named GRIM1, is isolated as a growth suppressor using genetic approaches[1]. SHQ1 codes for a human orthologue of yeast protein, Shq1p. Human SHQ1 contains an N-terminal CS domain that is similar to Shq1p and a C-terminal Shq1specific domain (SSD)[2]. A serine to proline substitution in SHQ1 suppresses box H/ACA RNA levels through sequestering NAF1 which is required for box H/ACA sno/ sca RNP biogenesis in mammalian cells[3]. Integrative genomic profiling reveals that the frequency of SHQ1 deletion in chromosome 3p of prostate cancer and cervical invasive carcinomas are 14.7% and 61%, respectively[4,5]. SHQ1 cooperates with PTEN to inhibit the development and metastasis of prostate cancer in mice[6]

Methods

Results

Conclusion