Hyperactivation of nuclear receptor coactivators induces PERK-dependent cell death

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

doi:10.18632/oncotarget.24451

Cited by 9 publications

(11 citation statements)

References 47 publications

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“…The details of the lentivirus generation has been described previously [ 24 ]. MCF7-Y537S cells were transduced with control (PLKO) and XBP1 shRNA lentivirus and selected using puromycin (1 μg/ml).…”

Section: Methodsmentioning

confidence: 99%

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XBP1 increases transactivation of somatic mutants of ESR1 and loss of XBP1 reverses endocrine resistance conferred by gain-of-function Y537S ESR1 mutation

Barua

Abbasi

Gupta

et al. 2020

Heliyon

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Somatic mutations of the estrogen receptor 1 gene (ESR1) is an emerging mechanism of acquired resistance to endocrine therapy in hormonal breast cancers. Hotspot point mutations in the ligand- binding domain of estrogen receptor α (ER) and genomic rearrangements producing ESR1 fusion genes are the two major types of mutations that are associated with endocrine resistance. The crosstalk between X-box binding protein 1 (XBP1), a key transcription factor of the unfolded protein response (UPR) and ER signalling creates a positive feedback loop that results in increased expression of XBP1 in ER-positive breast cancer. Here we report that XBP1 co-operated with point mutants (Y537S, D538G) and fusion mutants (ESR1-YAP1, ESR1-DAB2) of ESR1 to increase their transcriptional activity. XBP1 was required for optimal expression of estrogen-regulated genes, and up to 40% of XBP1-dependent genes were estrogen-responsive genes. Knockdown of XBP1 in genome-edited MCF7 cells expressing Y537S mutant reduced their growth, re-sensitized them to anti-estrogens and attenuated the constitutive and estrogen-stimulated expression of estrogen-regulated genes. Our study provides a rationale for overcoming endocrine resistance in breast cancers expressing ESR1 mutation by combining the XBP1 targeting agents with anti-estrogen agents.

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Section: Methodsmentioning

confidence: 99%

“…Cell proliferation using MTS assay has been described previously [ 24 ]. Briefly, cells (2,000/well) were plated in 96-well plate using complete DMEM media containing 5% FBS, and the following day, cells were either untreated or treated with the indicated compounds.…”

Section: Methodsmentioning

confidence: 99%

XBP1 increases transactivation of somatic mutants of ESR1 and loss of XBP1 reverses endocrine resistance conferred by gain-of-function Y537S ESR1 mutation

Barua

Abbasi

Gupta

et al. 2020

Heliyon

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“…The qRT-PCR used here has been described previously [13]. Brie y, Total RNA was isolated using Trizol (Invitrogen) and cDNA synthesis was carried out using ImProm-II™ Reverse Transcription System (Promega).…”

Section: Rna Extraction Cdna Synthesis and Qpcrmentioning

confidence: 99%

RRM2 and CDC6 are novel effectors of XBP1-mediated endocrine resistance and predictive markers of tamoxifen sensitivity

Barua

Sultana

Islam

et al. 2022

Preprint

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Background: The molecular mechanisms that determine endocrine resistance in estrogen receptor α (ER)-positive breast cancer patients are poorly understood. A positive feedback loop created by the intersection between estrogen signalling and unfolded protein response (UPR) leads to increased expression of x-box binding protein 1 (XBP1) and estrogen receptor α in ER-positive breast cancer. The endocrine-resistant breast cancers have elevated expression of XBP1 where it drives endocrine resistance by controlling the expression of its target genes. Despite the in-depth understanding about the biological functions of XBP1 in ER-positive breast cancer not much is known about the effectors of endocrine resistance downstream of XBP1. Methods and Results: We generated sub-clones of MCF7 cells with deletion of XBP1 using CRISPR-Cas9 for this study. Deletion of XBP1 compromised the upregulation of UPR-target genes during conditions of endoplasmic reticulum (EnR) stress and sensitized cells to EnR stress-induced cell death. Loss of XBP1 in MCF7 cells decreased cell growth, attenuated the induction of estrogen-responsive genes and sensitized them to anti-estrogen agents. The expression of cell cycle associated genes RRM2, CDC6, and TOP2A was significantly reduced upon XBP1 deletion/inhibition in several ER-positive breast cancer cells. Expression of RRM2, CDC6, and TOP2A was upregulated upon estrogen stimulation and elevated expression was observed in cells harbouring point-mutants (Y537S, D538G) of ESR1 in the steroid free conditions. Ectopic expression of RRM2 and CDC6 increased cell growth and reversed the hypersensitivity of XBP1 KO cells towards tamoxifen. Importantly, increased expression of XBP1-gene signature was associated with poor overall and relapse free survival, and reduced efficacy of tamoxifen treatment in ER-positive breast cancer. Conclusions: Our results suggest that expression of RRM2, CDC6 and TOP2A in ER-positive breast cancer is regulated by concerted effort of both ER and XBP1. RRM2 and CDC6 contribute to endocrine resistance downstream of XBP1 in ER-positive breast cancer. XBP1-gene signature was associated with poor outcome and response to tamoxifen in ER-positive breast cancer. Taken together these results reveal mechanistic insights about the role of XBP1 in endocrine resistant breast cancer.

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“…The UPR is therefore cytoprotective, allowing cells to adapt to perturbations that impinge on ER protein folding. However, during severe and prolonged ER stress, the UPR can become cytotoxic and induce apoptosis [ 2 , 3 ].…”

Section: Introductionmentioning

confidence: 99%

Downregulation of miR-17-92 Cluster by PERK Fine-Tunes Unfolded Protein Response Mediated Apoptosis

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Gupta

Cawley

et al. 2021

Life

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An important event in the unfolded protein response (UPR) is activation of the endoplasmic reticulum (ER) kinase PERK. The PERK signalling branch initially mediates a prosurvival response, which progresses to a proapoptotic response upon prolonged ER stress. However, the molecular mechanisms of PERK-mediated cell death are not well understood. Here we show that expression of the primary miR-17-92 transcript and mature miRNAs belonging to the miR-17-92 cluster are decreased during UPR. We found that miR-17-92 promoter reporter activity was reduced during UPR in a PERK-dependent manner. Furthermore, we show that activity of the miR-17-92 promoter is repressed by ectopic expression of ATF4 and NRF2. Promoter deletion analysis mapped the region responding to UPR-mediated repression to a site in the proximal region of the miR-17-92 promoter. Hypericin-mediated photo-oxidative ER damage reduced the expression of miRNAs belonging to the miR-17-92 cluster in wild-type but not in PERK-deficient cells. Importantly, ER stress-induced apoptosis was inhibited upon miR-17-92 overexpression in SH-SY5Y and H9c2 cells. Our results reveal a novel function for ATF4 and NRF2, where repression of the miR-17-92 cluster plays an important role in ER stress-mediated apoptosis. Mechanistic details are provided for the potentiation of cell death via sustained PERK signalling mediated repression of the miR-17-92 cluster.

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Hyperactivation of nuclear receptor coactivators induces PERK-dependent cell death

Cited by 9 publications

References 47 publications

XBP1 increases transactivation of somatic mutants of ESR1 and loss of XBP1 reverses endocrine resistance conferred by gain-of-function Y537S ESR1 mutation

XBP1 increases transactivation of somatic mutants of ESR1 and loss of XBP1 reverses endocrine resistance conferred by gain-of-function Y537S ESR1 mutation

RRM2 and CDC6 are novel effectors of XBP1-mediated endocrine resistance and predictive markers of tamoxifen sensitivity

Downregulation of miR-17-92 Cluster by PERK Fine-Tunes Unfolded Protein Response Mediated Apoptosis

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