Hyperactivation of nuclear receptor coactivators induces PERK-dependent cell death

// Muhammad Mosaraf Hossain 1 , David Barua 1 , Vahid Arabkari 1 , Nahidul Islam 2 , Ananya Gupta 3 and Sanjeev Gupta 1 1 Discipline of Pathology, School of Medicine, Lambe Institute for Translational Research, National University of Ireland Galway, Galway, Ireland 2 Regenerative Medicine Institute (REMEDI) at CURAM Centre for Research in Medical Devices, School of Medicine, College of Medicine, Nursing and Health Sciences, National University of Ireland Galway, Galway, Ireland 3 Discipline of Physiology, School of Medicine, National University of Ireland Galway, Galway, Ireland Correspondence to: Sanjeev Gupta, email: sanjeev.gupta@nuigalway.ie Keywords: steroid receptor coactivators; unfolded protein response; breast cancer; PERK; NCOA3 Received: November 03, 2017      Accepted: February 01, 2018      Published: February 08, 2018 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.