Hyperactivation of nuclear receptor coactivators induces PERK-dependent cell death.

Muhammad Mosaraf Hossain,Ananya Gupta,Sanjeev Gupta,Vahid Arabkari,Nahidul Islam,David Barua

doi:10.18632/oncotarget.24451

Muhammad Mosaraf Hossain, Ananya Gupta + Show 4 more

Open Access

https://doi.org/10.18632/oncotarget.24451

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Journal: Oncotarget	Publication Date: Feb 8, 2018
Citations: 7	License type: cc-by

Affiliation: Ollscoil na Gaillimhe – University of Galway

Abstract

Nuclear receptor coactivators (NCOAs) function as coactivators for nuclear receptors as well as several other transcription factors and potentiate their transcriptional activity. NCOAs play an important role in biology of hormone-dependent and -independent cancers. MCB-613 is a recently described, small molecule stimulator of NCOAs and anti-neoplastic compound that leads to the death of tumour cells due to increased cellular stress. In the present study we investigated the molecular mechanism of MCB-613-induced cell death. We report that absence of NCOA3 leads to compromised activation of PERK signalling pathway during unfolded protein response (UPR). We found that chemical and genetic inhibition of NCOA3 attenuated the expression of PERK at mRNA and protein level. We show that loss of NCOA3 renders cells hypersensitive to UPR induced cell death. Our results show that MCB-613 induced cell death is attenuated in NCOA3 knockout HeLa cells and MCB-613 leads to enhanced PERK signalling in wild-type HeLa cells. The knockdown of PERK provides resistance to MCB-613 mediated cell death while knockdown of XBP1 and ATF6 have no such effect. Our results suggest that hyperstimulation of NCOA3 by MCB-613 induces cell death by evoking constitutive PERK signalling. Taken together our results point to NCOA3 as an important determinant in regulating cell fate during ER stress, with too little and too much NCOA3 both producing deleterious effects.

Highlights

Nuclear receptor coactivators (NCOAs) are members of p160 family of coactivators that collaborate with nuclear receptors (NR) and other transcription factors to regulate gene expression [1]
To understand the mechanisms by which Nuclear receptor coactivator 3 (NCOA3) modulates the activation of PKR-like ER kinase (PERK)–eIF2α–ATF4 pathway we evaluated the expression of proximal mediators of PERK signalling during conditions of unfolded protein response (UPR) in presence and absence of NCOA3
We evaluated the expression of PERK, phosphoeIF2α and ATF4 proteins in pTRIPZ-shNCOA3-MCF7 cells that were either untreated or treated with (TG) thapsigargin in absence and presence of doxycycline

Summary

Introduction

Nuclear receptor coactivators (NCOAs) are members of p160 family of coactivators that collaborate with nuclear receptors (NR) and other transcription factors to regulate gene expression [1]. Since coactivators modulate the transcriptional activity of transcription factors, they exert broad genome-wide effects on gene expression networks and contribute significantly to a panorama of physiological and pathological processes [4]. Because of their strong connection with NRs, NCOA www.impactjournals.com/oncotarget proteins have been recognized as key oncoproteins in hormone-dependent cancers [5]. Increased expression of NCOA3 and NCOA1 has been reported in prostate cancers, and their high expression level is associated with tumour grade and disease recurrence [6]. Increased expression of NCOA3 is strongly correlated with shorter disease-free and overall survival in breast cancer [14]

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